Sulfoximine-substituted pyrimidines as CDK- and/or VEGF inhibitors, their production and use as pharmaceutical agents

ABSTRACT

This invention relates to pyrimidine derivatives of general formula I 
                         
in which Q, R 1 , R 2 , R 3 , R 4 , R 5 , X, and m have the meanings that are contained in the description, as inhibitors of cyclin-dependent kinases and VEGF-receptor tyrosine kinases, their production as well as their use as medications for treatment of various diseases.

This invention relates to sulfoximine-substituted pyrimidinederivatives, their process for production as well as their use asmedications for treating various diseases.

The cyclin-dependent kinases (cyclin-dependent kinase, CDK) are anenzyme family that plays an important role in the regulation of the cellcycle and thus represents an especially advantageous target for thedevelopment of small inhibitory molecules. Selective inhibitors of theCDKs can be used for the treatment of cancer or other diseases that arecaused by disorders of cell proliferation.

Receptor tyrosine kinases and their ligands, which specifically regulatethe function of endothelial cells, are involved decisively inphysiological as well as pathogenic angiogenesis. The VascularEndothelial Growth Factor (VEGF)/VEGF-receptor system is of specialimportance here. In pathological situations, which are accompanied byincreased neovascularization, such as, e.g., tumor diseases, anincreased expression of angiogenic growth factors and their receptorswas found Inhibitors of the VEGF/VEGF receptor system can inhibit thebuild-up of a blood vessel system in the tumor, thus separate the tumorfrom the oxygen and nutrient supply and thus inhibit tumor growth.

Pyrimidines and analogs are already described as active ingredients,such as, for example, the 2-anilino-pyrimidines as fungicides (DE4029650) or substituted pyrimidine derivatives for treatment ofneurological or neurodegenerative diseases (WO 99/19305). As CDKinhibitors, the most varied pyrimidine derivatives are described, forexample, bis(anilino)-pyrimidine derivatives (WO 00/12486),2-amino-4-substituted pyrimidines (WO 01/14375), purines (WO 99/02162),5-cyano-pyrimidines (WO 02/04429), anilinopyrimidines (WO 00/12486) and2-hydroxy-3-N,N-dimethylaminopropoxy-pyrimidines (WO 00/39101).

In particular, pyrimidine derivatives that exhibit inhibitory actionsrelative to CDKs were disclosed in WO 02/096888 and WO 03/7076437.Compounds that contain a phenylsulfonamide group are known as inhibitorsof the human carboanhydrases (especially carboanhydrase-2) and are usedas diuretics, i.a., for treating glaucoma. The nitrogen atom and theoxygen atoms of the sulfonamide bind via hydrogen bridges to the zinc²⁺ion and the amino acid Thr 199 in the active center of carboanhydrase-2and thus block their enzymatic function (A. Casini, F. Abbate, A.Scozzafava, C. T. Supuran, Bioorganic. Med. Chem L. 2003, 1, 2759.3). Anincrease of the specificity of the known CDK inhibitors by reduction orelimination of the inhibitory properties with respect to thecarboanhydrase could lead to an improvement of the pharmacologicalproperties and an alteration of the side effect spectrum.

Sulfoximines, such as, for example, sulfonimidoyl-modified triazoles asfungicides (H. Kawanishi, H. Morimoto, T. Nakano, T. Watanabe, K. Oda,K. Tsujihara, Heterocycles 1998, 49, 181) or arylalkylsulfoximines asherbicides and pesticides (Shell International Research, Ger. P. 2 129678) are described as active ingredients.

The object of this invention is to provide compounds that exhibit betterpharmaceutical properties, especially a reduction of carboanhydrase-2inhibition, than the already known CDK inhibitors.

It was now found that compounds of general formula (I)

in which

-   -   Q stands for the group

-   -   -   [or]

    -   D, E, G,

    -   L, M and T, in each case independently of one another, stand for        carbon, oxygen, nitrogen or sulfur,

    -   R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, CF₃, CN, nitro, or        for the group —COR⁸ or —O—C₁-C₆-alkyl,

    -   R² stands for hydrogen, or C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,        C₂-C₁₀-alkinyl, C₃-C₁₀-cycloalkyl, aryl or heteroaryl that is        optionally substituted in one or more places, in the same way or        differently, with hydroxy, halogen, C₁-C₆-alkoxy, amino, cyano,        C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl,        —C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,        C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl,        —N(C₁-C₆-alkyl)₂, C₁-C₆-alkanoyl, —CONR⁹R¹⁰, —COR⁸,        C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,        —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁸, —(CH₂)_(n)PO₃(R⁸)₂        or with the group —R⁶ or —NR⁹R¹⁰, and the phenyl,        C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and        —(CH₂)_(n)-heteroaryl itself optionally can be substituted in        one or more places, in the same way or differently, with        halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, or with the group        —CF₃ or —OCF₃, and the ring of C₃-C₁₀-cycloalkyl and        C₁-C₁₀-alkyl optionally can be interrupted by one or more        nitrogen, oxygen and/or sulfur atoms and/or can be interrupted        by one or more —C(O) groups in the ring and/or optionally one or        more possible double bonds can be contained in the ring,

    -   X stands for oxygen, sulfur, or for the group —NH— or        —N(C₁-C₃-alkyl)-

    -   or

    -   X and R² together form a C₃-C₁₀-cycloalkyl ring, which        optionally can contain one or more heteroatoms and optionally        can be substituted in one or more places, in the same way or        differently, with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen or        the group —NR⁹R¹⁰,

    -   R³ stands for hydroxy, halogen, CF₃, OCF₃ or for the group        —NR⁹R¹⁰, or for C₁-C₆-alkyl, C₃-C₆-cycloalkyl or C₁-C₆-alkoxy        that is optionally substituted in one or more places, in the        same way or differently, with halogen, hydroxy, C₁-C₆-alkoxy or        the group —NR⁹R¹⁰,

    -   m stands for 0-4,

    -   R⁴ stands for hydrogen or for the group —COR⁸, NO₂,        trimethylsilanyl (TMS), tert-butyl-dimethylsilanyl (TBDMS),        tert-butyl-diphenylsilanyl (TBDPS), triethylsilanyl (TES) or        —SO₂R⁷ or for C₁-C₁₀-alkyl or C₃-C₁₀-cycloalkyl that is        optionally substituted in one or more places, in the same way or        differently, with hydroxy, halogen, C₁-C₆-alkoxy,        C₁-C₆-alkylthio, cyano, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl,        C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl or with the group        —CONR⁹R¹⁰, —COR⁸, —CF₃, —OCF₃ or —NR⁹R¹⁰,

    -   R⁵ stands for C₁-C₁₀-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl or        C₃-C₁₀-cycloalkyl that is optionally substituted in one or more        places, in the same way or differently, with hydroxy,        C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, halogen or the group —NR⁹R¹⁰,

    -   or

    -   R⁴ and R⁵ together can form a C₅-C₁₀-cycloalkyl ring of group

-   -   -   whereby

    -   V, W and Y, in each case independently of one another, stand for        —CH₂— that is optionally substituted in one or more places, in        the same way or differently, with hydroxy, C₁-C₁₀-alkyl,        C₁-C₁₀-alkoxy or —NR⁹R¹⁰, whereby C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy        also can be substituted in one or more places, in the same way        or differently, with hydroxy, —NR⁹R¹⁰ or C₁-C₁₀-alkoxy and/or        -   can be interrupted by one or more —C(O)— groups in the ring,            and/or optionally one or more double bonds can be contained            in the ring,

    -   R⁶ stands for a heteroaryl or a C₃-C₁₀-cycloalkyl ring, which        optionally can contain one or more heteroatoms and optionally        can be substituted in one or more places, in the same way or        differently, with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen,

    -   R⁷ stands for C₁-C₁₀-alkyl or aryl that is optionally        substituted in one or more places, in the same way or        differently, with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or        with the group trimethylsilanyl (TMS) or —NR⁹R¹⁰,

    -   R⁸ stands for hydrogen, C₁-C₆-alkyl, hydroxy, C₁-C₆-alkoxy,        C₁-C₆-alkylthio, benzoxy or —NR⁹R¹⁰,

    -   R⁹ and R¹⁰, in each case independently of one another, stand for        hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy,        hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, phenyl, heteroaryl        or for the group —(CH₂)_(n)NR⁹R¹⁰, —CNHNH₂ or —NR⁹R¹⁰,

    -   or

    -   R⁹ and R¹⁰ together form a C₃-C₁₀-cycloalkyl ring that        optionally can be interrupted by one or more nitrogen, oxygen        and/or sulfur atoms and/or can be interrupted by one or more        —C(O)— groups in the ring and/or optionally one or more possible        double bonds can be contained in the ring, and

    -   n stands for 1-6,        as well as their isomers, diastereomers, enantiomers and/or        salts, are no longer able to inhibit carboanhydrases, whereby        they simultaneously inhibit cyclin-dependent kinases and VEGF        receptor tyrosine kinases already in the nanomolar range and        thus can inhibit the proliferation of tumor cells and/or tumor        angiogenesis.

Alkyl is defined in each case as a straight-chain or branched alkylradical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl,octyl, nonyl and decyl.

Alkoxy is defined in each case as a straight-chain or branched alkoxyradical, such as, for example, methyloxy, ethyloxy, propyloxy,isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy,isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy,undecyloxy or dodecyloxy.

Cycloalkyl is defined in each case as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

Heterocycloalkyl stands for an alkyl ring that comprises 3-12 carbonatoms, which instead of carbon contains one or more of the same ordifferent heteroatoms, such as, e.g., oxygen, sulfur or nitrogen.

As heterocycloalkyls, there can be mentioned, e.g.: oxiranyl, oxethanyl,aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl,dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, etc.

The ring systems, in which optionally one or more possible double bondscan be contained in the ring, are defined as, for example,cycloalkenyls, such as cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, or cycloheptenyl, whereby the linkage can be carried outboth to the double bond and to the single bonds.

Halogen is defined in each case as fluorine, chlorine, bromine oriodine.

The alkenyl substituents are in each case straight-chain or branched,whereby, for example, the following radicals are meant: vinyl,propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl,but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl,but-1-en-3-yl, ethinyl, prop-1-in-1-yl, but-1-in-1-yl, but-2-in-1-yl,but-3-en-1-yl, and allyl.

The aryl radical in each case has 6-12 carbon atoms, such as, forexample, naphthyl, biphenyl, and especially phenyl.

Heteroaryl is defined as a heteroaryl radical, which in each case canalso be benzocondensed. For example, thiophene, furan, oxazole,thiazole, imidazole, pyrazole, triazole, thia-4H-pyrazole, and benzoderivatives thereof can be mentioned as 5-ring heteroaromatic compounds,and pyridine, pyrimidine, triazine, quinoline, isoquinoline and theirbenzocondensed derivatives can be mentioned as 6-ring heteroaromaticcompounds.

Isomers are defined as chemical compounds of the same summation formulabut different chemical structure. In general, constitutional isomers andstereoisomers are distinguished.

Constitutional isomers have the same summation formula but aredistinguished by the way in which their atoms or groups of atoms arelinked. These include functional isomers, positional isomers, tautomersor valence isomers.

In principle, stereoisomers have the same structure (constitution)—andthus also the same summation formula—but are distinguished by thespatial arrangement of the atoms.

In general, configurational isomers and conformational isomers aredistinguished. Configurational isomers are stereoisomers that can beconverted into one another only by bond breaking. These includeenantiomers, diastereomers and E/Z (cis/trans) isomers.

Enantiomers are stereoisomers that behave toward one another like imageand mirror image and do not have any symmetry plane. All stereoisomersthat are not enantiomers are referred to as diastereomers. E/Z(cis/trans) isomers of double bonds are a special case.

Conformational isomers are stereoisomers that can be converted into oneanother by the turning of single bonds.

To differentiate the types of isomerism from one another, see also theIUPAC rules, Section E (Pure Appl. Chem. 45, 11-30, 1976).

If an acid group is included, the physiologically compatible salts oforganic and inorganic bases, such as, for example, the readily solublealkali salts and earth-alkaline salts, as well as N-methyl-glucamine,dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, and1-amino-2,3,4-butanetriol, are suitable as salts.

If a basic group is included, the physiologically compatible salts oforganic and inorganic acids, such as hydrochloric acid, sulfuric acid,phosphoric acid, citric acid, or tartaric acid, i.a., are suitable.

Those compounds of general formula (I), in which

-   -   Q stands for aryl,    -   R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, CF₃, CN, nitro, or        for the group —COR⁸ or —O—C₁-C₆-alkyl,    -   R² stands for hydrogen or C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,        C₂-C₁₀-alkinyl, C₃-C₁₀-cycloalkyl, aryl or heteroaryl that is        optionally substituted in one or more places, in the same way or        differently, with hydroxy, halogen, C₁-C₆-alkoxy, amino, cyano,        C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl,        —C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,        C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl,        —N(C₁-C₆-alkyl)₂, C₁-C₆-alkanoyl, —CONR⁹R¹⁰, —COR⁸,        C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,        —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁸, —(CH₂)_(n)PO₃(R⁸)₂        or with the group —R⁶ or —NR⁹R¹⁰, and the phenyl,        C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and        —(CH₂)_(n)-heteroaryl itself optionally can be substituted in        one or more places, in the same way or differently, with        halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group        —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl and the        C₁-C₁₀-alkyl optionally can be interrupted by one or more        nitrogen, oxygen and/or sulfur atoms and/or can be interrupted        by one or more —C(O) groups in the ring and/or optionally one or        more possible double bonds can be contained in the ring,    -   X stands for oxygen, sulfur, or for the group —NH—, or        —N(C₁-C₃-alkyl)-,    -   or    -   X and R² together form a C₃-C₁₀-cycloalkyl ring, which        optionally can contain one or more heteroatoms and optionally        can be substituted in one or more places with hydroxy,        C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen or the group —NR⁹R¹⁰,    -   R³ stands for hydroxy, halogen, CF₃, OCF₃ or for the group        —NR⁹R¹⁰, or for C₁-C₆-alkyl, C₃-C₆-cycloalkyl or C₁-C₆-alkoxy        that is optionally substituted in one or more places, in the        same way or differently, with halogen, hydroxy, C₁-C₆-alkoxy or        the group —NR⁹R¹⁰,    -   m stands for 0-4,    -   R⁴ stands for hydrogen or for the group —COR⁸, NO₂,        trimethylsilanyl (TMS), tert-butyl-dimethylsilanyl (TBDMS),        tert-butyl-diphenylsilanyl (TBDPS), triethylsilanyl (TES) or for        —SO₂R⁷, or for C₁-C₁₀-alkyl or C₃-C₁₀-cycloalkyl that is        optionally substituted in one or more places, in the same way or        differently, with hydroxy, halogen, C₁-C₆-alkoxy,        C₁-C₆-alkylthio, cyano, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl,        C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl or with the group        —CONR⁹R¹⁰, —COR⁸, —CF₃, —OCF₃ or —NR⁹R¹⁰,    -   R⁵ stands for C₁-C₁₀-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl or        C₃-C₁₀-cycloalkyl that is optionally substituted in one or more        places, in the same way or differently, with hydroxy,        C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, halogen, or the group —NR⁹R¹⁰,    -   or    -   R⁴ and R⁵ together can form a C₅-C₁₀-cycloalkyl ring of the        group

-   -   -   whereby

    -   V, W and Y, in each case, independently of one another, stands        for —CH₂— that is optionally substituted in one or more places,        in the same way or differently, with hydroxy, C₁-C₁₀-alkyl,        C₁-C₁₀-alkoxy or —NR⁹R¹⁰, whereby C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy        also can be substituted in one or more places, in the same way        or differently, with hydroxy, —NR⁹R¹⁰ or C₁-C₁₀-alkoxy and/or        -   can be interrupted by one or more —C(O)— groups in the ring,            and/or optionally one or more double bonds can be contained            in the ring,

    -   R⁶ stands for a heteroaryl or a C₃-C₁₀-cycloalkyl ring, which        optionally can contain one or more heteroatoms and optionally        can be substituted in one or more places, in the same way or        differently, with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen,

    -   R⁷ stands for C₁-C₁₀-alkyl or aryl that is optionally        substituted in one or more places, in the same way or        differently, with halogen, hydroxy, C₁-C₆-alkyl, or C₁-C₆-alkoxy        or with the group trimethylsilanyl (TMS) or —NR⁹R¹⁰,

    -   R⁸ stands for hydrogen, C₁-C₆-alkyl, hydroxy, C₁-C₆-alkoxy,        C₁-C₆-alkylthio, benzoxy or —NR⁹R¹⁰,

    -   R⁹ and R¹⁰, in each case independently of one another, stands        for hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy,        hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, phenyl, heteroaryl,        or for the group —(CH₂)_(n) NR⁹R¹⁰, —CNHNH₂ or —NR⁹R¹⁰,

    -   or

    -   R⁹ and R¹⁰ together form a C₃-C₁₀-cycloalkyl ring that        optionally can be interrupted by one or more nitrogen, oxygen        and/or sulfur atoms and/or can be interrupted by one or more        —C(O)— groups in the ring and/or optionally one or more possible        double bonds can be contained in the ring, and

    -   n stands for 1-6,        as well as their isomers, diastereomers, enantiomers and/or        salts,        are especially effective.

In addition, those compounds of general formula (I), in which

-   -   Q stands for phenyl,    -   R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, CF₃, CN, nitro or        for the group —COR⁸ or —O—C₁-C₆-alkyl,    -   R² stands for hydrogen or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,        C₂-C₁₀-alkinyl, C₃-C₁₀-cycloalkyl, aryl or heteroaryl that is        optionally substituted in one or more places, in the same way or        differently, with hydroxy, halogen, C₁-C₆-alkoxy, amino, cyano,        C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl,        —C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,        C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl,        —N(C₁-C₆-alkyl)₂, C₁-C₆-alkanoyl, —CONR⁹R¹⁰, —COR⁸,        C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,        —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁸, —(CH₂)_(n)PO₃(R⁸)₂        or with the group —R⁶ or —NR⁹R¹⁰, and phenyl, C₃-C₁₀-cycloalkyl,        aryl, heteroaryl, —(CH₂)_(n)-aryl and —(CH₂)_(n)-heteroaryl        itself optionally can be substituted in one or more places, in        the same way or differently, with halogen, hydroxy, C₁-C₆-alkyl,        C₁-C₆-alkoxy, or with the group —CF₃ or —OCF₃, and the ring of        C₃-C₁₀-cycloalkyl and C₁-C₁₀-alkyl optionally can be interrupted        by one or more nitrogen, oxygen and/or sulfur atoms, and/or can        be interrupted by one or more —C(O)— groups in the ring, and/or        optionally one or more possible double bonds can be contained in        the ring,    -   X stands for oxygen, sulfur, or for the group —NH— or        —N(C₁-C₃-alkyl)-,    -   or    -   X and R² together form a C₃-C₁₀-cycloalkyl ring, which        optionally can contain one or more heteroatoms, and optionally        can be substituted in one or more places with hydroxy,        C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen or the group —NR⁹R¹⁰,    -   R³ stands for hydroxy, halogen, CF₃, OCF₃ or for the group        —NR⁹R¹⁰ or for C₁-C₆-alkyl, C₃-C₆-cycloalkyl or C₁-C₆-alkoxy        that is optionally substituted in one or more places, in the        same way or differently, with halogen, hydroxy, C₁-C₆-alkoxy or        the group —NR⁹R¹⁰,    -   m stands for 0-2,    -   R⁴ stands for hydrogen or for the group —COR⁸, NO₂,        trimethylsilanyl (TMS), tert-butyl-dimethylsilanyl (TBDMS),        tert-butyl-diphenylsilanyl (TBDPS), triethylsilanyl (TES) or        —SO₂R⁷, or for C₁-C₁₀-alkyl or C₃-C₁₀-cycloalkyl that is        optionally substituted in one or more places, in the same way or        differently, with hydroxy, halogen, C₁-C₆-alkoxy,        C₁-C₆-alkylthio, cyano, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl,        C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl or with the group        —CONR⁹R¹⁰, —COR⁸, —CF₃, —OCF₃ or —NR⁹R¹⁰,    -   R⁵ stands for C₁-C₁₀-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl or        C₃-C₁₀-cycloalkyl that is optionally substituted in one or more        places, in the same way or differently, with hydroxy,        C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, halogen or the group —NR⁹R¹⁰,    -   or    -   R⁴ and R⁵ together can form a C₅-C₁₀-cycloalkyl ring of the        group

-   -    whereby    -   V, W, and Y, in each case independently of one another, stand        for —CH₂— that is optionally substituted in one or more places,        in the same way or differently, with hydroxy, C₁-C₁₀-alkyl,        C₁-C₁₀-alkoxy or —NR⁹R¹⁰, whereby C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy        also can be substituted in one or more places, in the same way        or differently, with hydroxy, —NR⁹R¹⁰ or C₁-C₁₀-alkoxy, and/or        -   can be interrupted by one or more —C(O)— groups in the ring,            and/or optionally one or more double bonds can be contained            in the ring,    -   R⁶ stands for a heteroaryl or a C₃-C₁₀-cycloalkyl ring, which        optionally can contain one or more heteroatoms, and optionally        can be substituted in one or more places, in the same way or        differently, with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen,    -   R⁷ stands for C₁-C₁₀-aryl or aryl that is optionally substituted        in one or more places, in the same way or differently, with        halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group        trimethylsilanyl (TMS) or —NR⁹R¹⁰,    -   R⁸ stands for hydrogen, C₁-C₆-alkyl, hydroxy, C₁-C₆-alkoxy,        C₁-C₆-alkylthio, benzoxy or —NR⁹R¹⁰,    -   R⁹ and R¹⁰, in each case independently of one another, stand for        hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy,        hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, phenyl, heteroaryl        or for the group —(CH₂)_(n)NR⁹R¹⁰, —CNHNH₂ or —NR⁹R¹⁰,    -   or    -   R⁹ and R¹⁰ together form a C₃-C₁₀-cycloalkyl ring, which        optionally can be interrupted by one or more nitrogen, oxygen        and/or sulfur atoms and/or can be interrupted by one or more        —C(O)— groups in the ring and/or optionally one or more possible        double bonds can be contained in the ring, and    -   n stands for 1-6,        as well as their isomers, diastereomers, enantiomers and/or        salts,        are especially effective.

In particular, those compounds of general formula (I) in which

-   -   Q stands for phenyl,    -   R¹ stands for hydrogen, halogen, CN, NO₂ or CF₃,    -   R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkinyl, aryl or heteroaryl        that is optionally substituted in one or more places, in the        same way or differently, with hydroxy, halogen, C₁-C₆-alkyl,        C₁-C₆-alkoxy, C₂-C₆-alkinyl or with the group —COR⁸,    -   X stands for oxygen, sulfur or for the group —NH—,    -   R³ stands for halogen, hydroxy or C₁-C₆-alkyl or C₁-C₆-alkoxy        that is optionally substituted in one or more places with        halogen or hydroxy,    -   m stands for 0-2,    -   R⁴ stands for hydrogen or for the group NO₂, —CO—R⁸, —SO₂R⁷ or        for C₁-C₁₀-alkyl that is optionally substituted in one or more        places, in the same way or differently, with halogen or hydroxy,    -   R⁵ stands for C₁-C₁₀-alkyl or C₃-C₁₀-cycloalkyl that is        optionally substituted in one or more places, in the same way or        differently, with hydroxy or C₃-C₁₀-cycloalkyl,    -   or    -   R⁴ and R⁵ together can form a C₅-C₁₀-cycloalkyl ring of the        group

-   -    whereby    -   V, W and Y, in each case independently of one another, stand for        —CH₂— that is optionally substituted in one or more places, in        the same way or differently, with hydroxy, C₁-C₁₀-alkyl,        C₁-C₁₀-alkoxy or —NR⁹R¹⁰, whereby C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy        also can be substituted in one or more places, in the same way        or differently, with hydroxy, —NR⁹R¹⁰ or C₁-C₁₀-alkoxy and/or        -   can be interrupted by one or more —C(O)— groups in the ring            and/or optionally one or more double bonds can be contained            in the ring,    -   R⁷ stands for C₁-C₁₀-alkyl that is optionally substituted in one        or more places, in the same way or differently, with the group        trimethylsilanyl (TMS),    -   R⁸ stands for hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy or        C₃-C₆-cycloalkyl, which optionally can be substituted in one or        more places with C₁-C₆-alkyl,    -   n stands for 1,        as well as their isomers, diastereomers, enantiomers and/or        salts,        are effective.

In addition, those compounds of general formula (I), in which

-   -   Q stands for phenyl,    -   R¹ stands for hydrogen or halogen,    -   R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkinyl or aryl that is        optionally substituted in one or more places, in the same way or        differently, with hydroxy, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy,        C₂-C₆-alkinyl or with the group —COR⁸,    -   X stands for oxygen, sulfur or for the group —NH—,    -   R³ stands for halogen or C₁-C₆-alkyl or C₁-C₆-alkoxy that is        optionally substituted in one or more places with halogen,    -   m stands for 0-2,    -   R⁴ stands for hydrogen or for the group NO₂, —CO—R⁸, —SO₂R⁷ or        for C₁-C₁₀-alkyl,    -   R⁵ stands for C₁-C₁₀-alkyl or C₃-C₁₀-cycloalkyl that is        optionally substituted in one or more places, in the same way or        differently, with hydroxy or C₃-C₁₀-cycloalkyl,    -   R⁷ stands for C₁-C₁₀-alkyl that is optionally substituted in one        or more places, in the same way or differently, with the group        trimethylsilanyl (TMS),    -   R⁸ stands for hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy or        C₃-C₆-cycloalkyl, which optionally can be substituted in one or        more places with C₁-C₆-alkyl,        as well as their isomers, diastereomers, enantiomers and/or        salts,        are especially effective.

In addition, specially selected compounds of general formula (I) arethose in which

-   -   Q stands for phenyl,    -   R¹ stands for hydrogen or halogen,    -   R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkinyl or aryl that is        optionally substituted in one or more places, in the same way or        differently, with hydroxy, halogen, methyl, methoxy, ethinyl or        with the group —COH or —COCH₃,    -   X stands for oxygen, sulfur or for the group —NH—,    -   R³ stands for halogen, methyl, methoxy or —CF₃,    -   m stands for 0-2,    -   R⁴ stands for hydrogen, methyl or for the group NO₂, —COOC₂H₅ or        —SO₂C₂H₄—SI(CH₃)₃,    -   R⁵ stands for methyl, ethyl, cyclopropyl, cyclopentyl,        —(CH₂)-cyclopropyl or hydroxyethyl,        as well as their isomers, diastereomers, enantiomers and/or        salts.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the roles of CDKs and cyclins in the cell cycle.

The compounds according to the invention essentially inhibitcyclin-dependent kinases, upon which their action is based, for example,against cancer, such as solid tumors and leukemia; auto-immune diseases,such as psoriasis, alopecia and multiple sclerosis; chemotherapyagent-induced alopecia and mucositis; cardiovascular diseases, such asstenoses, arterioscleroses and restenoses; infectious diseases, such as,e.g., those caused by unicellular parasites, such as trypanosoma,toxoplasma or plasmodium, or those caused by fungi; nephrologicaldiseases, such as, e.g., glomerulonephritis; chronic neurodegenerativediseases, such as Huntington's disease, amyotrophic lateral sclerosis,Parkinson's disease, AIDS dementia and Alzheimer's disease; acuteneurodegenerative diseases, such as ischemias of the brain andneurotraumas; and viral infections, such as, e.g., cytomegalicinfections, herpes, hepatitis B and C, and HIV diseases.

The eukaryotic cell division cycle ensures the duplication of the genomeand its distribution to the daughter cells by passing through acoordinated and regulated sequence of events. The cell cycle is dividedinto four successive phases: the G1 phase represents the time before theDNA replication, in which the cell grows and is sensitive to externalstimuli. In the S phase, the cell replicates its DNA, and in the G2phase, preparations are made for entry into mitosis. In mitosis (Mphase), the replicated DNA separates, and cell division is complete.

The cyclin-dependent kinases (CDKs), a family of serine/threoninekinases, whose members require the binding of a cyclin (Cyc) as aregulatory subunit in order for them to activate, drive the cell throughthe cell cycle. Different CDK/Cyc pairs are active in the various phasesof the cell cycle. CDK/Cyc pairs that are important to the basicfunction of the cell cycle are, for example, CDK4(6)/CycD, CDK2/CycE,CDK2/CycA, CDK1/CycA and CDK1/CycB. Some members of the CDK enzymefamily have a regulatory function by influencing the activity of theabove-mentioned cell cycle CDKs, while no specific function could beassociated with other members of the CDK enzyme family. One of thelatter, CDK5, is distinguished in that it has an atypical regulatorysubunit (p35) that deviates from the cyclins, and its activity ishighest in the brain.

The entry into the cell cycle and the passage through the “restrictionpoints,” which marks the independence of a cell from further growthsignals for the completion of the cell division that has begun, arecontrolled by the activity of the CDK4(6)/CycD and CDK2/CycE complexes.The essential substrate of these CDK complexes is the retinoblastomaprotein (Rb), the product of the retinoblastoma tumor suppressor gene.Rb is a transcriptional co-repressor protein. In addition to other,still largely little understood mechanisms, Rb binds and inactivatestranscription factors of the E2F type and forms transcriptionalrepressor complexes with histone-deacetylases (HDAC) (Zhang, H. S. etal. (2000). Exit from G1 and S Phase of the Cell Cycle is Regulated byRepressor Complexes Containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell101, 79-89). By the phosphorylation of Rb by CDKs, bonded E2Ftranscription factors are released and result in transcriptionalactivation of genes, whose products are required for the DNA synthesisand the progression through the S-phase. In addition, theRb-phosphorylation brings about the breakdown of the Rb-HDAC complexes,by which additional genes are activated. The phosphorylation of Rb byCDKs is to be treated as equivalent to exceeding the “restrictionpoints.” For the progression through the S-phase and its completion, theactivity of the CDK2/CycE and CDK2/CycA complexes is necessary, e.g.,the activity of the transcription factors of the E2F type is turned offby means of phosphorylation by CDK2/CycA as soon as the cells areentered into the S-phase. After replication of DNA is complete, the CDK1in the complex with CycA or CycB controls the entry into and the passagethrough phases G2 and M (FIG. 1).

According to the extraordinary importance of the cell-division cycle,the passage through the cycle is strictly regulated and controlled. Theenzymes that are necessary for the progression through the cycle must beactivated at the correct time and are also turned off again as soon asthe corresponding phase is passed. Corresponding control points(“checkpoints”) stop the progression through the cell cycle if DNAdamage is detected, or the DNA replication or the creation of thespindle device is not yet completed.

The activity of the CDKs is controlled directly by various mechanisms,such as synthesis and degradation of cyclins, complexing of the CDKswith the corresponding cyclins, phosphorylation and dephosphorylation ofregulatory threonine and tyrosine radicals, and the binding of naturalinhibitory proteins. While the amount of protein of the CDKs in aproliferating cell is relatively constant, the amount of the individualcyclins oscillates with the passage through the cycle. Thus, forexample, the expression of CycD during the early G1 phase is stimulatedby growth factors, and the expression of CycE is induced after the“restriction points” are exceeded by the activation of the transcriptionfactors of the E2F type. The cyclins themselves are degraded by theubiquitin-mediated proteolysis. Activating and inactivatingphosphorylations regulate the activities of the CDKs, for examplephosphorylate CDK-activating kinases (CAKs) Thr160/161 of the CDK1,while, by contrast, the families of Wee1/Myt1 inactivate kinases CDK1 byphosphorylation of Thr14 and Tyr15. These inactivating phosphorylationscan be destroyed in turn by cdc25 phosphatases. The regulation of theactivity of the CDK/Cyc complexes by two families of natural CDKinhibitor proteins (CKIs), the protein products of the p21 gene family(p21, p27, p57) and the p16 gene family (p15, p16, p18, p19) is verysignificant. Members of the p21 family bind to cyclin complexes of CDKs1, 2, 4, 6, but inhibit only the complexes that contain CDK1 or CDK2.Members of the p16 family are specific inhibitors of the CDK4- and CDK6complexes.

The plane of control point regulation lies above this complex directregulation of the activity of the CDKs. Control points allow the cell totrack the orderly sequence of the individual phases during the cellcycle. The most important control points lie at the transition from G1to S and from G2 to M. The G1 control point ensures that the cell doesnot initiate any DNA synthesis unless it has proper nutrition, interactscorrectly with other cells or the substrate, and its DNA is intact. TheG2/M control point ensures the complete replication of DNA and thecreation of the mitotic spindle before the cell enters into mitosis. TheG1 control point is activated by the gene product of the p53 tumorsuppressor gene. p53 is activated after detection of changes inmetabolism or the genomic integrity of the cell and can trigger either astopping of the cell cycle progression or apoptosis. In this case, thetranscriptional activation of the expression of the CDK inhibitorprotein p21 by p53 plays a decisive role. A second branch of the G1control point comprises the activation of the ATM and Chk1 kinases afterDNA damage by UV light or ionizing radiation and finally thephosphorylation and the subsequent proteolytic degradation of the cdc25Aphosphatase (Mailand, N. et al. (2000). Rapid Destruction of Humancdc25A in Response to DNA Damage. Science 288, 1425-1429). A shutdown ofthe cell cycle results from this, since the inhibitory phosphorylationof the CDKs is not removed. After the G2/M control point is activated bydamage of the DNA, both mechanisms are involved in a similar way instopping the progression through the cell cycle.

The loss of the regulation of the cell cycle and the loss of function ofthe control points are characteristics of tumor cells. The CDK-Rb signalpath is affected by mutations in over 90% of human tumor cells. Thesemutations, which finally result in inactivating phosphorylation of theRB, include the over-expression of D- and E-cyclins by geneamplification or chromosomal translocations, inactivating mutations ordeletions of CDK inhibitors of the p16 type, as well as increased (p27)or reduced (CycD) protein degradation. The second group of genes, whichare affected by mutations in tumor cells, codes for components of thecontrol points. Thus p53, which is essential for the G1 and G2/M controlpoints, is the most frequently mutated gene in human tumors (about 50%).In tumor cells that express p53 without mutation, it is ofteninactivated because of a greatly increased protein degradation. In asimilar way, the genes of other proteins that are necessary for thefunction of the control points are affected by mutations, for exampleATM (inactivating mutations) or cdc25 phosphatases (over-expression).

Convincing experimental data indicate that CDK2/Cyc complexes occupy adecisive position during the cell cycle progression: (1) Bothdominant-negative forms of CDK2, such as the transcriptional repressionof the CDK2 expression by anti-sense oligonucleotides, produce astopping of the cell cycle progression. (2) The inactivation of the CycAgene in mice is lethal. (3) The disruption of the function of theCDK2/CycA complex in cells by means of cell-permeable peptides resultedin tumor cell-selective apoptosis (Chen, Y. N. P. et al. (1999).Selective Killing of Transformed Cells by Cyclin/Cyclin-Dependent Kinase2 Antagonists. Proc. Natl. Acad. Sci. USA 96, 4325-4329).

Changes of the cell cycle control play a role not only in carcinoses.The cell cycle is activated by a number of viruses, both by transformingviruses as well as by non-transforming viruses, to make possible thereproduction of viruses in the host cell. The false entry into the cellcycle of normally post-mitotic cells is associated with variousneurodegenerative diseases.

The mechanisms of the cell cycle regulation, their changes in diseasesand a number of approaches to develop inhibitors of the cell cycleprogression and especially the CDKs were already described in a detailedsummary in several publications (Sielecki, T. M. et al. (2000).Cyclin-Dependent Kinase Inhibitors: Useful Targets in Cell CycleRegulation. J. Med. Chem. 43, 1-18; Fry, D. W. & Garrett, M. D. (2000)Inhibitors of Cyclin-Dependent Kinases as Therapeutic Agents for theTreatment of Cancer. Curr. Opin. Oncol. Endo. Metab. Invest. Drugs 2,40-59; Rosiania, G. R. & Chang, Y. T. (2000). TargetingHyperproliferative Disorders with Cyclin-Dependent Kinase Inhibitors.Exp. Opin. Ther. Patents 10, 215-230; Meijer, L. et al. (1999).Properties and Potential Applications of Chemical Inhibitors ofCyclin-Dependent Kinases. Pharmacol. Ther. 82, 279-284; Senderowicz, A.M. & Sausville, E. A. (2000). Preclinical and Clinical Development ofCyclin-Dependent Kinase Modulators. J. Natl. Cancer Inst. 92, 376-387).

To use the compounds according to the invention as pharmaceuticalagents, the latter are brought into the form of a pharmaceuticalpreparation, which in addition to the active ingredient for enteral orparenteral administration contains suitable pharmaceutical, organic orinorganic inert support media, such as, for example, water, gelatin, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc. The pharmaceutical preparations can bepresent in solid form, for example as tablets, coated tablets,suppositories, or capsules, or in liquid form, for example as solutions,suspensions, or emulsions. Moreover, they optionally contain adjuvants,such as preservatives, stabilizers, wetting agents or emulsifiers; saltsfor changing the osmotic pressure, or buffers. These pharmaceuticalpreparations are also subjects of this invention.

For parenteral administration, especially injection solutions orsuspensions, especially aqueous solutions of active compounds inpolyhydroxyethoxylated castor oil, are suitable.

As carrier systems, surface-active adjuvants such as salts of bile acidsor animal or plant phospholipids, but also mixtures thereof as well asliposomes or their components, can also be used.

For oral administration, especially tablets, coated tablets or capsuleswith talc and/or hydrocarbon vehicles or binders, such as, for example,lactose, corn or potato starch, are suitable. The administration canalso be carried out in liquid form, such as, for example, as a juice, towhich optionally a sweetener is added.

Enteral, parenteral and oral administrations are also subjects of thisinvention.

The dosage of the active ingredients can vary depending on the method ofadministration, age and weight of the patient, type and severity of thedisease to be treated and similar factors. The daily dose is 0.5-1000mg, preferably 50-200 mg, whereby the dose can be given as a single doseto be administered once or divided into two or more daily doses.

In contrast, compounds of general formula I according to the inventioncan also inhibit receptor tyrosine kinases and their ligands thatspecifically regulate the function of endothelial cells. Receptortyrosine kinases and their ligands that specifically regulate thefunction of endothelial cells are involved decisively in physiologicalas well as pathogenic angiogenesis. The VEGF/VEGF-receptor system is ofspecial importance here. In pathological situations, which areaccompanied by increased neovascularization, an increased expression ofangiogenic growth factors and their receptors was found. Most solidtumors thus express large amounts of VEGF, and the expression of theVEGF receptors is preferably considerably increased in the endothelialcells that lie near the tumors or run through the latter (Plate et al.,Cancer Res. 53, 5822-5827, 1993). The inactivation of the VEGF/VEGFreceptor system by VEGF-neutralizing antibodies (Kim et al., Nature 362,841-844, 1993), retroviral expression of dominant-negative VEGF-receptorvariants (Millauer et al., Nature 367, 576-579, 1994), recombinantVEGF-neutralizing receptor variants (Goldman et al., Proc. Natl. Acad.Sci. USA 95, 8795-8800, 1998), or low-molecular inhibitors of theVEGF-receptor tyrosine kinase (Fong et al., Cancer Res. 59, 99-106,1999; Wedge et al., Cancer Res. 60, 970-975, 2000; Wood et al., CancerRes. 60, 2178-2189, 2000) resulted in a reduced tumor growth and areduced tumor vascularization. Thus, the inhibition of the angiogenesisis a possible treatment method for tumor diseases.

Compounds according to the invention can consequently inhibit eithercyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6,CDK7, CDK8 and CDK9, as well as the glycogen-synthase-kinase (GSK-3β)and VEGF-receptor tyrosine kinases or cyclin-dependent kinases orVEGF-receptor tyrosine kinases. These actions contribute to the factthat the compounds according to the invention can be used in thetreatment of cancer, angiofibroma, arthritis, eye diseases, auto-immunediseases, chemotherapy agent-induced alopecia and mucositis, Crohn'sdisease, endometriosis, fibrotic diseases, hemangioma, cardiovasculardiseases, infectious diseases, nephrological diseases, chronic and acuteneurodegenerative diseases, as well as injuries to the nerve tissue,viral infections, for inhibiting the reocclusion of vessels afterballoon catheter treatment, in vascular prosthetics or after mechanicaldevices are used to keep vessels open, such as, e.g., stents, asimmunosuppressive agents, for supporting scar-free healing, in senilekeratosis and in contact dermatitis, whereby

cancer is defined as solid tumors, tumor or metastastic growth, Kaposi'ssarcoma, Hodgkin's disease, and leukemia;

arthritis is defined as rheumatoid arthritis;

eye diseases are defined as diabetic retinopathy, and neovascularglaucoma;

auto-immune diseases are defined as psoriasis, alopecia and multiplesclerosis;

fibrotic diseases are defined as cirrhosis of the liver, mesangial cellproliferative diseases, and arteriosclerosis;

infectious diseases are defined as diseases that are caused byunicellular parasites;

cardiovascular diseases are defined as stenoses, such as, e.g.,stent-induced restenoses, arterioscleroses and restenoses;

nephrological diseases are defined as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombic microangiopathicsyndrome, transplant rejections and glomerulopathy;

chronic neurodegenerative diseases are defined as Huntington's disease,amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia andAlzheimer's disease;

acute neurodegenerative diseases are defined as ischemias of the brainand neurotraumas;

and viral infections are defined as cytomegalic infections, herpes,hepatitis B or C, and HIV diseases.

Subjects of this invention are also pharmaceutical agents for treatingthe above-cited diseases, which contain at least one compound accordingto general formula (I), as well as pharmaceutical agents with suitableformulation substances and vehicles.

The compounds of general formula I according to the invention are, i.a.,excellent inhibitors of the cyclin-dependent kinases, such as CDK1,CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, as well as theglycogen-synthase-kinase (GSK-3β).

The intermediate products of general formula (IIa) or (IIb), preferablyused for the production of the compounds of general formula I accordingto the invention,

in which Z stands for —NH₂ or NO₂ and m, R³, R⁴ and R⁵ have the meaningsthat are indicated in general formula (I), as well as their isomers,diastereomers, enantiomers and salts as intermediate products, are alsosubjects of this invention.

The intermediate products of general formula (IIIa), (IIIb) or (IIIc),also preferably used for the production of the compounds of generalformula I according to the invention,

in which W stands for halogen, hydroxy or X—R², and R¹, R², R³, R⁵, mand X have the meanings that are indicated in general formula (I), aswell as their isomers, diastereomers, enantiomers, and salts asintermediate products for the production of the compound of generalformula (I).

Intermediate products of general formula (IV), preferably used for theproduction of the compounds of general formula (I) according to theinvention,

in which

Hal stands for halogen, W stands for halogen, hydroxy, or X—R², and R¹,R², and X have the meanings that are indicated in general formula (I),as well as their isomers, diastereomers, enantiomers and salts, are alsosubjects of this invention.

If the production of the starting compounds is not described, the latterare known or can be produced in a way that is similar to known compoundsor to processes that are described here. It is also possible to performall reactions that are described here in parallel reactors or by meansof combinatory operating procedures.

The isomer mixtures can be separated into enantiomers or E/Z isomersaccording to commonly used methods, such as, for example,crystallization, chromatography or salt formation.

The production of salts is carried out in the usual way by a solution ofthe compound of formula I being mixed with the equivalent amount of oran excess of a base or acid, which optionally is in solution, and theprecipitate being separated or the solution being worked up in the usualway.

Production of the Compounds According to the Invention

One of the most important methods for the production of sulfoximines isthe reaction of a sulfoxide with hydrazoic acid, which is produced insitu, e.g., from the reaction of sodium azide and concentrated sulfuricacid (M. Reggelin, C. Zur, Synthesis 2000, 1, 1). The reaction can beperformed in an organic solvent, such as chloroform. Other methods forthe synthesis of sulfoximines are, e.g., the reactions of sulfoxideswith

-   -   a) TsN₃ ((a) R. Tanaka, K. Yamabe, J. Chem. Soc. Chem. Commun.        1983, 329; (b) H. Kwart, A. A. Kahn, J. Am. Chem. Soc. 1967, 89,        1959)).    -   b) N-Tosylimino Phenyl Iodinane and Cat. Amounts of        Cu(I)triflate (J. F. K. Müller, P. Vogt, Tetrahedron Lett. 1998,        39, 4805)    -   c) Boc-azide and Cat. Amounts of Iron(II) Chloride (T. Bach, C.        Korber, Tetrahedron Lett. 1998, 39, 5015) or    -   d) o-Mesitylenesulfonylhydroxylamine (MSH) (C. R. Johnson, R. A.        Kirchhoff, H. G. Corkins, J. Org. Chem. 1974, 39, 2458).    -   e) [N-(2-(Trimethylsilyl)ethanesulfonyl)imino]phenyliodinane        (PhI═NSes) (S. Cren, T. C. Kinahan, C. L. Skinner and H. Tye,        Tetrahedron Lett. 2002, 43, 2749).

In terms of structure and configuration, sulfoximines generally have ahigh stability (C. Bolm, J. P. Hildebrand, J. Org. Chem. 2000, 65, 169).These properties of the functional group often also allow drasticreaction conditions and make possible the simple derivatization of thesulfoximines in the imine-nitrogen and α-carbon. Enantiomer-puresulfoximines are also used as auxiliaries in the diastereoselectivesynthesis ((a) S. G. Pyne, Sulfur Reports 1992, 12, 57; (b) C. R.Johnson, Aldrichchimica Acta 1985, 18, 3). The production ofenantiomer-pure sulfoximines is described, e.g., via the racematecleavage with enantiomer-pure camphor-10-sulfonic acid ((a) C. R.Johnson, C. W. Schroeck, J. Am. Chem. Soc. 1973, 95, 7418; (b) C. S.Shiner, A. H. Berks, J. Org. Chem. 1988, 53, 5543). Another method forproducing optically active sulfoximines consists in the stereoselectiveimination of optically active sulfoxides with use of MSH ((a) C. Bolm,P. Müller, K. Harms, Acta Chem. Scand. 1996, 50, 305; (b) Y. Tamura, J.Minamikawa, K. Sumoto, S. Fujii, M. Ikeda, J. Org. Chem. 1973, 38,1239).

The following examples explain the production of the compounds accordingto the invention without limiting the scope of the claimed compounds tothese examples.

The substituents Q, R¹, R², R³, R⁴, R⁵ and m have the meaning that isindicated in general formula (I).

EXAMPLE 1.0 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1-methylethyl)amino]pyridimin-3-yl}amino)phenyl]-S-methylsulfoximide

METHOD A

40 mg (0.23 mmol) of (RS)—S-(4-aminophenyl)-S-methyl sulfoximide and 62mg (0.23 mmol) of(R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propan-1-ol are mixed underargon with 0.5 ml of 1-butyl-3-methyl-imidazolium tetrafluoroborate(survey article on ionic liquids: a) T. Welton, Chem. Rev. 1999, 99,2071 b) H. Zhao, Aldrichimica Acta 2002, 35, 75 c) M. J. Earle, K. R.Seddon, ACS Symposium Series 2002, 819, 10) and stirred for 10 minutesat room temperature. The reaction mixture is heated to 60° C. andstirred for another 3 hours at this temperature. It is mixed with 0.08ml of a 4 molar solution of hydrochloric acid in dioxane and stirred for60 hours at 60° C. After cooling, the reaction mixture is mixed with 10ml of ethyl acetate and stirred for 10 minutes. The organic solvent isdecanted, and the residue is dissolved in 10 ml of methanol. It is mixedwith 200 ml of ethyl acetate and then washed with 50 ml of a saturatedNaCl solution. The organic phase is dried (Na₂SO₄), filtered andconcentrated by evaporation. The remaining residue is purified bychromatography (DCM/ethanol, 8:2). 23 mg (0.06 mmol, corresponding to26% of theory) of the product is obtained.

METHOD B

A solution of 267 mg (1.0 mmol) of(R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propan-1-ol in 2 ml ofacetonitrile is added at room temperature to 171 mg (1.0 mmol) of(RS)—S-(4-aminophenyl)-S-methyl sulfoximide in 1 ml of acetonitrile. Thebatch is mixed with 0.25 ml of a 4 molar solution of hydrochloric acidin dioxane and stirred under reflux overnight. The solvent is drawn off,and the remaining residue is purified by chromatography (DCM/EtOH 8:2).The crude product that is obtained is finally purified by HPLC:

Column: Luna C18(2) 5μ

Length×ID: 150×21.2 mm

Eluants: A=H₂O, B=ACN, A/0.5 g of NH₄Ac/l

Flow: 10.0 ml/min

Gradient: 5→100% B(5′)-5→100% B(30′)+100% B(5′)

Detector: PDA 214 nm

Temperature: 21° C.

RT in min: 20.3

53 mg (0.13 mmol, corresponding to 13% of theory) of the product isobtained.

¹H-NMR (DMSO): 9.71 (s, 1H), 8.11 (s, 1H), 7.91 (d, 2H), 7.78 (d, 2H),6.41 (d, 1H), 4.89 (t, 1H), 4.25 (m, 1H), 3.96 (br, 1H), 3.53 (m, 2H),3.03 (s, 3H), 1.21 (d, 3H).

MS: 400 (ES).

EXAMPLE 1.1 Production of(RS)—S-[3-({5-bromo-4-[(R)-(2-hydroxy-1-methylethyl)amino]pyrimidin-2-yl}amino)phenyl]-S-methyl-N-nitrosulfoximide

A solution of 37 mg (0.17 mmol) of(RS)—S-(3-aminophenyl)-S-methyl-N-nitrosulfoximide in 3 ml ofacetonitrile is mixed with 91 mg (0.34 mmol) of(R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propan-1-ol and 0.06 ml ofa 4 molar solution of hydrochloric acid in dioxane, and it is stirredunder reflux overnight. Another 0.05 ml of the 4 molar solution ofhydrochloric acid in dioxane is added, and it is refluxed for another 6hours. After TLC monitoring, it is mixed again with 92 mg (0.34 mmol) of(R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propan-1-ol and refluxedovernight. After cooling, the batch is made basic with saturated NaHCO₃solution and extracted from ethyl acetate. The combined organic phasesare dried (Na₂SO₄), filtered and concentrated by evaporation. Theresidue that is obtained is purified by chromatography (DCM/EtOH 95:5).24 mg (0.05 mmol, corresponding to 32% of theory) of the product isobtained (diastereomers A/B 1:1).

¹H-NMR (DMSO): 9.85 (s, 2H, A+B), 8.73 (m, 1H, A), 8.69 (m, 1H, B), 8.11(s, 1H, A), 8.10 (s, 1H, B), 7.92 (m, 2H, A+B), 7.58 (m, 4H, A+B), 6.40(m, 2H, A+B), 4.86 (t, 2H, A+B), 4.32 (m, 2H, A+B), 3.68 (s, 3H, A),3.66 (s, 3H, B), 3.55 (m, 4H, A+B), 1.23 (d, 3H, A), 1.21 (d, 3H, B).

MS: 445 (ES).

Produced in a way similar to the above-described process variants arealso the compounds below:

EXAMPLE 1.2 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-(2-hydroxy-1-methylpropyl)amino]pyridimin-2-yl}amino)phenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 9.73 (s, 1H), 8.12 (s, 1H), 7.91 (d, 2H), 7.86 (d, 2H),6.14 (d, 1H), 5.02 (br, 1H), 4.09 (m, 1H), 3.97 (s, 1H), 3.78 (m, 1H),3.02 (s, 3H), 1.25 (d, 3H), 1.09 (d, 3H).

MS: 414 (ES).

EXAMPLE 1.3 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 9.72 (s, 1H), 8.11 (s, 1H), 7.90 (d, 2H), 7.78 (d, 2H),6.10 (d, 1H), 4.87 (s, 1H), 4.07 (m, 1H), 3.98 (s, 1H), 3.01 (s, 3H),1.19 (m, 9H).

MS: 428 (ES).

EXAMPLE 1.4 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-2-hydroxy-1-methylpropoxy]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 10.12 (s, 1H), 8.45 (s, 1H), 7.92 (d, 2H), 7.84 (d, 2H),5.21 (m, 1H), 4.91 (d, 1H), 4.04 (s, 1H), 3.87 (m, 1H), 3.03 (s, 3H),1.28 (d, 3H), 1.13 (d, 3H).

MS: 415 (ES).

EXAMPLE 1.5 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-cyclopropyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide

95 mg (0.32 mmol) of(R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol isdissolved in 2 ml of acetonitrile and mixed with 116 mg (0.32 mmol) of(RS)—S-(4-aminophenyl)-S-cyclopropyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide.After 0.08 ml of an approximately 4N solution of HCl in dioxane and 0.08ml of water are added, the mixture is heated in a sealed vessel for 16hours to 75° C. The suspension is filtered, and the filtrate isseparated by flash chromatography(dichloromethane—dichloromethane/ethanol 95:5, 15 ml/min) The fractions,43-51 min, contain 50 mg (25% of theory) of the desired product.

¹H-NMR (DMSO): 9.91 (s, 1H), 8.16 (s, 1H), 8.01 (d, 2H), 7.83 (d, 2H),6.14 (d, 1H), 4.87 (s, 1H), 4.10 (m, 1H), 3.18 (m, 1H), 2.92 (m, 2H),1.37-1.00 (m, 4H), 1.21 (s, 3H), 1.20 (d, 3H), 1.14 (s, 3H), 0.93 (m,2H), 0.01 (s, 9H).

MS: 618/620 (100%, ES).

EXAMPLE 1.6 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-cyclopropylsulfoximideMETHOD C

50 mg of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]-pyrimidin-2-yl}amino)phenyl]-S-cyclopropyl-N-[2-(trimethylsilyl)ethylsulfonyl]-sulfoximideis dissolved in 1 ml of tetrahydrofuran and mixed with 0.3 ml of a 1 Msolution of tetrabutylammonium fluoride in tetrahydrofuran. The mixtureis stirred for 3 days at 50° C. and purified by flash chromatography(dichloromethane—dichloromethane/ethanol 9:1). 10 mg (28% of theory) ofthe product is obtained.

¹H-NMR (DMSO): 9.72 (s, 1H), 8.13 (s, 1H), 7.90 (d, 2H), 7.74 (d, 2H),6.10 (d, 1H), 4.86 (s, 1H), 4.10 (m, 1H), 3.95 (s, 1H), 3.16 (m, 1H),1.40-1.00 (m, 4H), 1.20 (s, 3H), 1.19 (d, 3H), 1.15 (s, 3H).

MS: 454/456 (20%, ES).

Produced in a way similar to the above-described process variants arealso the compounds below.

EXAMPLE 1.7 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1-methylethyl)amino]pyrimidin-2-yl}amino)phenyl]-S-(cyclopropylmethyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide

¹H-NMR (DMSO): 10.33 (s, 1H), 8.23 (s, 1H), 8.01 (d, 2H), 7.88 (d, 2H),7.02 (d, 1H), 5.58 (s br, 1H), 4.28 (m, 1H), 3.67 (d, 2H), 3.55 (m, 2H),2.98 (m, 2H), 1.21 (d, 3H), 0.97 (m, 2H), 0.86 (m, 1H), 0.44 (m, 2H),0.12 (m, 2H), 0.01 (s, 9H)

MS: 604/606 (100%, ES).

Melting point: 195° C. (dec.).

EXAMPLE 1.8 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-(cyclopropylmethyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide

¹H-NMR (DMSO): 9.93 (s, 1H), 8.16 (s, 1H), 8.02 (d, 2H), 7.83 (d, 2H),6.14 (d, 1H), 4.87 (s, 1H), 4.10 (m, 1H), 3.64 (d, 2H), 2.96 (m, 2H),1.21 (s, 3H), 1.20 (d, 3H), 1.15 (s, 3H), 0.98 (m, 2H), 0.87 (m, 1H),0.46 (m, 2H), 0.13 (m, 2H), 0.02 (s, 9H).

MS: 632/634 (40%, ES).

EXAMPLE 1.9 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-(cyclopropylmethyl)sulfoximide

¹H-NMR (DMSO): 9.73 (s, 1H), 8.13 (s, 1H), 7.92 (d, 2H), 7.75 (d, 2H),6.10 (d, 1H), 4.85 (s, 1H), 4.10 (m, 1H), 3.92 (s, 1H), 3.02 (m, 2H),1.20 (s, 3H), 1.19 (d, 3H), 1.14 (s, 3H), 0.87 (m, 1H), 0.37 (m, 2H),0.00 (m, 2H).

EXAMPLE 1.10 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-cyclopentyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide

Melting point: 200-201° C.

EXAMPLE 1.11 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-cyclopentylsulfoximide

Melting point: 194-196° C.

1.12 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)-amino]pyrimidin-2-yl}amino)phenyl]-S-(2-hydroxyethyl)-N-[2-(trimethylsilyl)-ethylsulfonyl]sulfoximide

A solution of 200 mg (0.55 mmol) of(RS)—S-(4-aminophenyl)-S-(2-hydroxyethyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximidein 2 ml of acetonitrile and 0.5 ml of water is mixed with 0.17 ml of a4N solution of HCl in dioxane. 198 mg (0.67 mmol) of(R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol in 1.5ml of acetonitrile is added, and the batch is stirred for 20 hours at80° C. The solvent is removed, and the remaining residue is purified bychromatography (DCM/EtOH 9:1). 148 mg (0.24 mmol, corresponding to 44%of theory) of the product is obtained.

¹H-NMR (DMSO): 10.21 (s, 1H), 8.21 (s, 1H), 7.97 (m, 2H), 7.85 (m, 2H),6.42 (d, 1H), 4.10 (m, 1H), 3.80 (m, 2H), 3.70 (m, 2H), 2.95 (m, 2H),1.20 (m, 9H), 0.96 (m, 2H), 0.03 (s, 9H).

EXAMPLE 1.13 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-(2-hydroxyethyl)-sulfoximide

¹H-NMR (DMSO): 9.75 (s, 1H), 8.13 (s, 1H), 7.91 (m, 2H), 7.75 (m, 2H),6.12 (d, 1H), 4.85 (m, 2H), 4.11 (m, 2H), 3.65 (m, 2H), 3.23 (m, 2H),1.17 (m, 9H).

The diastereomer mixture that is obtained is cleaved into purediastereomers by means of preparatory HPLC.

Column: Chiralpak AD 20μ

Length×ID: 250×60 mm

Eluants: Hexane/ethanol 70:30

Flow: 80 ml/min

Detector: UV 300 nm

Temperature: Room temperature

RT in min: 23.41; Diastereomer 1 (Example 1.14)

-   -   54.16; Diastereomer 2 (Example 1.15)

1.16 Production of(RS)—S-[4-({5-Bromo-4-[(1R,2R)-(2-hydroxy-1-methyl-propyl)amino]pyrimidin-2-yl}amino)phenyl]-S-(2-hydroxyethyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide

¹H-NMR (DMSO): 10.53 (s, 1H), 8.28 (s, 1H), 7.95 (m, 2H), 7.88 (m, 2H),6.86 (d, 1H), 4.13 (m, 1H), 3.76 (m, 5H), 2.90 (m, 2H), 1.25 (d, 3H),1.11 (d, 3H), 0.93 (m, 2H), 0.03 (s, 9H).

1.17 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-(2-hydroxy-1-methyl-propyl)amino]pyrimidin-2-yl}amino)phenyl]-S-(2-hydroxyethyl)sulfoximide

¹H-NMR (DMSO): 9.75 (s, 1H), 8.11 (s, 1H), 7.92 (m, 2H), 7.72 (m, 2H),6.14 (d, 1H), 5.02 (d, 1H), 4.85 (tr, 1H), 4.10 (m, 2H), 3.78 (m, 1H),3.62 (m, 2H), 3.22 (m, 2H), 1.23 (d, 3H), 1.08 (d, 3H).

MS: 444 (ES).

The diastereomer mixture that is obtained is cleaved into the purediastereomers by means of preparatory HPLC:

Column: Chiralpak AD-H 5μ

Length×ID: 250×20 mm

Eluants: A: Hexane, C: Ethanol

Flow: 10 ml/min

Gradient: Isocratic 50% C

Detector: UV 300 nm

Temperature: Room temperature

RT in min: 13.1; Diastereomer 1 (Example 1.18)

-   -   18.9; Diastereomer 2 (Example 1.19)

1.20 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-2-hydroxy-1-methyl-propoxy]pyrimidin-2-yl}amino)phenyl]-S-(2-hydroxyethyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide

A solution of 205 mg (0.56 mmol) of(RS)—S-(4-aminophenyl)-S-(2-hydroxyethyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximidein 2 ml of acetonitrile is mixed with 0.15 ml of a 4N solution of HCl indioxane. 175 mg (0.62 mmol) of(2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)oxy]-butan-2-ol in 2 ml ofacetonitrile is added, and the batch is stirred for 24 hours at 70° C.Then, it is stirred for another 24 hours at 85° C. The solvent isremoved, and the remaining residue is purified by chromatography(DCM/EtOH 9:1). 110 mg (0.18 mmol, corresponding to 32% of theory) ofthe product is obtained.

¹H-NMR (DMSO): 10.31 (s, 1H), 8.45 (s, 1H), 7.99 (m, 2H), 7.83 (m, 2H),5.25 (m, 1H), 4.93 (m, 2H), 3.75 (m, 5H), 2.90 (m, 2H), 1.32 (d, 3H),1.13 (d, 3H), 0.93 (m, 2H), 0.05 (s, 9H).

MS: 609 (ES).

1.21 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-2-hydroxy-1-methyl-propoxy]pyrimidin-2-yl}amino)phenyl]-S-(2-hydroxyethyl)sulfoximide

Column: Kromasil C8 5μ

Length×ID: 125×20 mm

Eluants: A: H₂O+0.1% NH₃, B: ACN

Flow: 15 ml/min

Gradient: 24→38% B(10′)→95(1′)

Detector: UV 300 nm

Temperature: Room temperature

RT in min: 10.9

¹H-NMR (DMSO): 10.10 (s, 1H), 8.42 (s, 1H), 7.88 (m, 2H), 7.77 (m, 2H),5.23 (m, 1H), 4.88 (d, 1H), 4.85 (tr, 1H), 4.18 (s, 1H), 3.84 (m, 1H),3.63 (m, 2H), 3.22 (m, 2H), 1.28 (d, 3H), 1.14 (d, 3H).

MS: 445 (ES).

EXAMPLE 1.22 Production of(RS)—S-[3-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

127 mg (0.43 mmol) of(R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol in 1ml of acetonitrile is added to 74 mg (0.43 mmol) of(RS)—S-(3-aminophenyl)-S-methyl sulfoximide in 0.5 ml of acetonitrile.It is mixed with 0.1 ml of a 4N solution of HCl in dioxane, and thebatch is refluxed overnight. The solvent is drawn off, and the remainingresidue is purified by chromatography (DCM/EtOH 9:1). 37 mg (0.09 mmol,corresponding to 20% of theory) of the product is obtained.

¹H-NMR (DMSO): 9.65 (s, 1H), 8.75 (m, 1H), 8.08 (s, 1H), 7.64 (m, 1H),7.42 (m, 2H), 6.04 (m, 1H), 4.82 (br, 1H), 4.20 (m, 1H), 4.06 (m, 1H),3.03 (s, 3H), 1.18 (m, 9H).

MS: 428 (ES).

EXAMPLE 1.23 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)-2-methoxyphenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 9.32 (s, 1H), 8.49 (m, 1H), 8.02 (s, 1H), 7.64 (m, 1H),7.15 (m, 1H), 5.97 (d, 1H), 4.81 (s, 1H), 4.19 (m, 1H), 4.06 (m, 1H),3.87 (s, 3H), 3.15 (s, 3H), 1.15 (m, 9H).

MS: 458 (ES).

EXAMPLE 1.24 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-2-hydroxy-1-methylpropoxy]pyrimidin-2-yl}amino)-2-methoxyphenyl]-S-methylsulfoximide

220 mg (1.1 mmol) of (RS)—S-(4-amino-2-methoxyphenyl)-S-methylsulfoximide and 280 mg (1.0 mmol) of(2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)oxy]-butan-2-ol in 10 ml ofacetonitrile are mixed with 0.28 ml of a 4N solution of HCl in dioxaneand stirred under reflux overnight. It is mixed with 1 ml of a solutionof n-butanol/methanol (9:1) and stirred under reflux for another 5 days.The batch is concentrated by evaporation, and the residue is purified bychromatography (DCM/ethanol 8:2). 36 mg (0.1 mmol, corresponding to 8%of theory) of the product is obtained.

¹H-NMR (DMSO): 9.81 (s, 1H), 8.32 (m, 2H), 7.71 (m, 1H), 7.18 (m, 1H),5.25 (m, 1H), 4.95 (br, 1H), 4.18 (m, 1H), 3.91 (s, 3H), 3.83 (m, 1H),3.15 (s, 3H), 1.25 (m, 3H), 1.10 (m, 3H).

MS: 445 (ES).

EXAMPLE 1.25 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-(2-hydroxy-1-methylpropyl)amino]pyrimidin-2-yl}amino)-2-methoxyphenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 9.37 (s, 1H), 8.43 (m, 1H), 8.02 (s, 1H), 7.70 (m, 1H),7.14 (m, 1H), 5.98 (d, 1H), 5.01 (d, 1H), 4.20 (m, 1H), 4.07 (s, 1H),3.87 (s, 3H), 3.75 (m, 1H), 3.14 (s, 3H), 1.15 (d, 3H), 1.07 (d, 3H).

MS: 444 (ES).

The diastereomer mixture that is obtained is cleaved into purediastereomers by means of preparatory HPLC:

Column: Chiralpak AD 20μ

Length×ID: 250×60 mm

Eluants: A=Hexane, B=ethanol

Flow: 80 ml/min

Gradient: Isocratic 50% B

Detector: UV 280 nm

Temperature: Room temperature

RT in min: 20.3; Diastereomer 1 (Example 1.26)

-   -   34.8; Diastereomer 2 (Example 1.27)

EXAMPLE 1.28 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-(2-hydroxy-1-methylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-N,S-dimethyl-sulfoximide

¹H-NMR (DMSO): 9.73 (s, 1H), 8.11 (s, 1H), 7.96 (m, 2H), 7.65 (m, 2H),6.14 (d, 1H), 5.01 (d, 1H), 4.10 (m, 1H), 3.79 (m, 1H), 3.05 (s, 3H),2.46 (s, 3H), 1.25 (d, 3H), 1.12 (d, 3H).

MS: 428 (ES)

The diastereomer mixture that is obtained is cleaved into the purediastereomers by means of preparatory HPLC:

Column: Chiralpak AD-H 5μ

Length×ID: 250×4.6 mm

Eluants: A=Hexane, B=Ethanol A/0.1% DEA

Flow: 15 ml/min

Gradient: Isocratic 15% B

Detector: UV 300 nm

Temperature: Room temperature

RT in min: 25.45; Diastereomer 1 (Example 1.29)

-   -   29.32; Diastereomer 2 (Example 1.30)

EXAMPLE 1.31 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-N-(ethoxycarbonyl)-S-methylsulfoximide

600 mg (2.48 mmol) of (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide and 610 mg (2.07 mmol) of(R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol in 8ml of acetonitrile are mixed with 0.52 ml of water and 0.52 ml of a 4Nsolution of HCl in dioxane. The batch is stirred for 24 hours at 60° C.and then concentrated by evaporation. The remaining residue is purifiedby chromatography (DCM/EtOH 8:2). 649 mg (1.30 mmol, corresponding to53% of theory) of the product is obtained.

¹H-NMR (DMSO): 10.10 (s, 1H), 8.20 (s, 1H), 7.97 (m, 2H), 7.85 (m, 2H),6.39 (d, 1H), 4.10 (m, 1H), 3.91 (m, 2H), 3.30 (s, 3H), 1.10 (m, 12H).

EXAMPLE 1.32 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-(2-hydroxy-1-methylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-N-(ethoxycarbonyl)-S-methylsulfoximide

¹H-NMR (DMSO): 9.88 (s, 1H), 8.13 (s, 1H), 7.98 (m, 2H), 7.79 (m, 2H),6.18 (d, 1H), 5.01 (d, 1H), 4.10 (m, 1H), 3.90 (q, 2H), 3.78 (m, 1H),3.41 (s, 3H), 1.21 (d, 3H), 1.08 (m, 6H).

EXAMPLE 1.33 Production of(RS)—S-{4-[(5-bromo-4-{[(1R,2R)-2-hydroxy-1-(methoxymethyl)propyl]amino}pyrimidin-2-yl)amino]phenyl}-N-(ethoxycarbonyl)-S-ethylsulfoximide

¹H-NMR (DMSO): 9.92 (s, 1H), 8.17 (s, 1H), 7.99 (m, 2H), 7.70 (m, 2H),6.08 (d, 1H), 5.12 (m, 1H), 4.20 (m, 1H), 4.00 (m, 1H), 3.89 (m, 2H),3.50 (m, 4H), 3.28 (s, 3H), 1.08 (m, 9H).

EXAMPLE 1.34 Production of(RS)—S-{4-[(5-bromo-4-{[(1R,2R)-2-hydroxy-1-(methoxymethyl)propyl]amino}pyrimidin-2-yl)amino]phenyl}-N-(ethoxycarbonyl)-S-methylsulfoximide

¹H-NMR (DMSO): 9.91 (s, 1H), 8.17 (s, 1H), 7.95 (m, 2H), 7.78 (m, 2H),6.08 (d, 1H), 5.13 (m, 1H), 4.20 (m, 1H), 3.95 (m, 3H), 3.48 (m, 2H),3.40 (s, 3H), 3.27 (s, 3H), 1.10 (m, 6H).

EXAMPLE 1.35 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-N-(ethoxycarbonyl)-S-ethylsulfoximide

¹H-NMR (DMSO): 9.89 (s, 1H), 8.14 (s, 1H), 7.99 (m, 2H), 7.72 (m, 2H),6.13 (d, 1H), 4.84 (s, 1H), 4.09 (m, 1H), 3.90 (m, 2H), 3.54 (q, 2H),1.15 (m, 15H).

EXAMPLE 1.36 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-(2-hydroxy-1-methylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-N-(ethoxycarbonyl)-S-ethylsulfoximide

¹H-NMR (DMSO): 9.92 (s, 1H), 8.13 (s, 1H), 7.97 (m, 2H), 7.72 (m, 2H),6.27 (d, 1H), 4.10 (m, 1H), 9.92 (m, 2H), 3.80 (m, 1H), 3.55 (q, 2H),1.23 (d, 3H), 1.10 (m, 9H).

EXAMPLE 1.37 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)-2-methylphenyl]-N-(ethoxycarbonyl)-S-methylsulfoximide

¹H-NMR (DMSO): 9.98 (s, 1H), 8.18 (s, 1H), 7.75 (m, 3H), 6.22 (d, 1H),4.05 (m, 1H), 3.88 (q, 2H), 3.39 (s, 3H), 2.57 (s, 3H), 1.15 (m, 12H).

MS: 514 (ES).

EXAMPLE 1.38 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-(2-hydroxy-1-methylpropyl)amino]pyrimidin-2-yl}amino)-2-methylphenyl]-N-(ethoxycarbonyl)-S-methylsulfoximide

¹H-NMR (DMSO): 9.88 (s, 1H), 8.13 (s, 1H), 7.79 (m, 3H), 6.33 (d, 1H),4.04 (m, 1H), 3.90 (q, 2H), 3.82 (m, 1H), 3.30 (s, 3H), 2.62 (s, 3H),1.22 (d, 3H), 1.08 (m, 6H).

EXAMPLE 1.39 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-2-hydroxy-1-methylpropoxy]pyrimidin-2-yl}amino)phenyl]-N-(ethoxycarbonyl)-S-ethylsulfoximide

128 mg (0.51 mmol) of (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-ethylsulfoximide and 150 mg (0.53 mmol) of(2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)oxy]-butan-2-ol in 2 ml ofacetonitrile are mixed with 0.12 ml of a 4N solution of HCl in dioxane.The batch is stirred for 2 days at 60° C. The solvent is removed, andthe residue is purified by chromatography (DCM/EtOH 95:5). 43 mg (0.09mmol, corresponding to 17% of theory) of the product is obtained.

¹H-NMR (DMSO): 10.28 (s, 1H), 8.45 (s, 1H), 7.99 (m, 2H), 7.78 (m, 2H),5.22 (m, 1H), 4.91 (d, 1H), 3.88 (m, 3H), 3.53 (q, 2H), 1.30 (d, 3H),1.10 (m, 9H).

EXAMPLE 1.40 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-2-hydroxy-1-methylpropoxy]pyrimidin-2-yl}amino)phenyl]-N-(ethoxycarbonyl)-S-methylsulfoximide

¹H-NMR (DMSO): 10.24 (s, 1H), 8.45 (s, 1H), 7.97 (m, 2H), 7.85 (m, 2H),5.22 (m, 1H), 4.91 (d, 1H), 3.90 (m, 3H), 3.43 (s, 3H), 1.30 (d, 3H),1.11 (m, 6H).

METHOD D EXAMPLES 1.41/1.42 Production and Separation into thediastereomers of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide (Example 1.3)

1.65 g (3.30 mmol) of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-N-(ethoxycarbonyl)-S-methylsulfoximide in 6.5 ml of ethanol is mixed with 19.1 ml (6.69 mmol) of a0.35 molar solution of NaOEt in ethanol and stirred under reflux for 5hours. The batch is stirred overnight at room temperature and then addedto a saturated NaCl solution. It is extracted with ethyl acetate, andthe combined organic phases are dried (Na₂SO₄), filtered andconcentrated by evaporation. The remaining residue is purified bychromatography (DCM/EtOH 9:1). 0.95 g (2.22 mmol, corresponding to 67%of theory) of the product is obtained.

The analytical data are similar to those of Example 1.3 from ProcessVariant 1, Method A.

The diastereomer mixture is cleaved into the diastereomers by means ofpreparatory HPLC:

Column: Chiralpak OJ 20μ

Length×ID: 290×50.8 mm

Eluants: A=Hexane+0.1% DEA, B=ethanol

Flow: 80 ml/min

Gradient: Isocratic 15% B

Detector: UV 300 nm

Temperature: Room temperature

RT in min: 29.4; Diastereomer 1 (Example 1.41)

-   -   37.1; Diastereomer 2 (Example 1.42)

Similarly produced are:

EXAMPLES 1.43/1.44 Production and Separation into the diastereomers of(RS)—S-[4-({5-bromo-4-[(1R,2R)-(2-hydroxy-1-methylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide (Example 1.2)

The analytical data are similar to those of Example 1.2 from ProcessVariant 1, Method A.

The diastereomer mixture is cleaved into the diastereomers by means ofpreparatory HPLC:

Column: Chiralpak OJ 20μ

Length×ID: 290×50.8 mm

Eluants: A=Hexane+0.1% DEA, B=ethanol

Flow: 80 ml/min

Gradient: Isocratic 15% B

Detector: UV 280 nm

Temperature: Room temperature

RT in min: 44.6; Diastereomer 1 (Example 1.43)

-   -   57.3; Diastereomer 2 (Example 1.44)

EXAMPLE 1.45 Production of(RS)—S-{4-[(5-bromo-4-{[(1R,2R)-2-hydroxy-1-(methoxymethyl)-propyl]amino}pyrimidin-2-yl)amino]phenyl}-S-methylsulfoximide

¹H-NMR (DMSO): 9.77 (s, 1H), 8.14 (s, 1H), 7.91 (m, 2H), 7.76 (m, 2H),6.05 (d, 1H), 5.12 (br, 1H), 4.20 (m, 1H), 3.98 (m, 2H), 3.49 (m, 2H),3.29 (s, 3H), 3.02 (s, 3H), 1.19 (d, 3H).

The diastereomer mixture is cleaved into the diastereomers by means ofpreparatory HPLC:

Column: Chiralcel OJ 20μ

Length×ID: 290×50.8 mm

Eluants: Hexane/ethanol 80:20

Flow: 80.0 ml/min

Detector: UV 300 nm

Temperature: Room temperature

RT in min: 47.55: Diastereomer 1 (Example 1.46)

-   -   61.02: Diastereomer 2 (Example 1.47)

EXAMPLE 1.48 Production of(RS)—S-{4-[(5-bromo-4-{[(1R,2R)-2-hydroxy-1-(methoxymethyl)-propyl]amino}pyrimidin-2-yl)amino]phenyl}-S-ethylsulfoximide

¹H-NMR (DMSO): 9.78 (s, 1H), 8.14 (s, 1H), 7.94 (m, 2H), 7.70 (m, 2H),6.05 (d, 1H), 5.11 (d, 1H), 4.19 (m, 1H), 3.97 (m, 2H), 3.50 (m, 2H),3.30 (s, 3H), 3.05 (q, 2H), 1.07 (m, 6H).

The diastereomer mixture is cleaved into the diastereomers by means ofpreparatory HPLC:

Column: Chiralcel OJ 20μ

Length×ID: 290×50.8 mm

Eluants: Hexane:ethanol 80:20

Flow: 80 ml/min

Detector: UV 300 nm

Temperature: Room temperature

RT in min: 45.5: Diastereomer 1 (Example 1.49)

-   -   53.1: Diastereomer 2 (Example 1.50)

EXAMPLE 1.51 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-(2-hydroxy-1-methylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-ethylsulfoximide

¹H-NMR (DMSO): 9.71 (s, 1H), 8.11 (s, 1H), 7.90 (m, 2H), 7.71 (m, 2H),6.13 (d, 1H), 5.01 (d, 1H), 4.08 (m, 1H), 3.93 (s, 1H), 3.78 (m, 1H),3.03 (q, 2H), 1.22 (d, 3H), 1.10 (m, 6H).

The diastereomer mixture is cleaved into the diastereomers by means ofpreparatory HPLC:

Column: Chiracel OJ 20μ

Length×ID: 250×50.8 mm

Eluants: A: Hexane+0.1% DEA; B: Ethanol

Flow: 80 ml/min

Gradient: Isocratic 15% B

Detector: UV 300 nm

Temperature: Room temperature

RT in min: 34.0: Diastereomer 1 (Example 1.52)

-   -   43.7: Diastereomer 2 (Example 1.53)

EXAMPLE 1.54 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)phenyl]-S-ethylsulfoximide

¹H-NMR (DMSO): 9.74 (s, 1H), 8.13 (s, 1H), 7.92 (m, 2H), 7.71 (m, 2H),6.09 (d, 1H), 4.84 (s, 1H), 4.08 (m, 1H), 3.92 (s, 1H), 3.06 (q, 2H),1.15 (m, 12H).

The diastereomer mixture is cleaved into the diastereomers by means ofpreparatory HPLC:

Column: Chiralpak AD 20μ

Length×ID: 250×60 mm

Eluants: Hexane/2-Propanol 80:20

Flow: 80/100 ml/min

Detector: UV 280 nm

Temperature: Room temperature

RT in min: 222.2: Diastereomer 1 (Example 1.55)

-   -   249.8: Diastereomer 2 (Example 1.56)

EXAMPLE 1.57 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)-2-methylphenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 9.63 (s, 1H), 8.11 (s, 1H), 7.81 (m, 2H), 7.63 (m, 1H),6.08 (d, 1H), 4.88 (s, 1H), 4.06 (m, 2H), 3.03 (s, 3H), 2.67 (s, 3H),1.2 (m, 9H).

MS: 442 (ES).

The diastereomer mixture is cleaved into the diastereomers by means ofpreparatory HPLC:

Column: Chiralpak AS 20μ

Length×ID: 250×50.8 mm

Eluants: A=Hexane, B=Ethanol

Flow: 80 ml/min

Gradient: Isocratic 15% B

Detector: UV 300 nm

Temperature: Room temperature

RT in min: 18.96; Diastereomer 1 (Example 1.58)

-   -   21.56; Diastereomer 2 (Example 1.59)

EXAMPLE 1.60 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-(2-hydroxy-1-methylpropyl)amino]pyrimidin-2-yl}amino)-2-methylphenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 9.62 (s, 1H), 8.11 (s, 1H), 7.82 (m, 2H), 7.66 (m, 1H),6.14 (d, 1H), 5.02 (d, 1H), 4.04 (m, 2H), 3.80 (m, 1H), 3.03 (s, 3H),2.65 (s, 3H), 1.22 (d, 3H), 1.10 (d, 3H).

The diastereomer mixture is cleaved into the diastereomers by means ofpreparatory HPLC:

Column: Chiralpak AD 20μ

Length×ID: 250×50.8 mm

Eluants: A: Hexane+0.1% DEA, B: Ethanol

Flow: 80 ml/min

Gradient: Isocratic 25% B

Detector: UV 280 nm

Temperature: Room temperature

RT in min: 104, Diastereomer 1 (Example 1.61)

-   -   124, Diastereomer 2 (Example 1.62)

EXAMPLE 1.63 Production of(RS)—S-{4-[(5-bromo-4-ethoxypyrimidin-2-yl)amino]phenyl}-S-ethylsulfoximide

28 mg (0.056 mmol) of(RS)—S-[4-({5-bromo-4-[(1R,2R)-2-hydroxy-1-methylpropoxy]pyrimidin-2-yl}amino)phenyl]-N-(ethoxycarbonyl)-S-methylsulfoximide in 0.11 ml of ethanol is mixed with 0.32 ml (0.113 mmol) ofa 0.35 molar solution of NaOEt in ethanol and stirred under reflux for 6hours. The batch is stirred overnight at room temperature, and thenadded to a saturated NaCl solution. It is extracted with ethyl acetate,and the combined organic phases are dried (Na₂SO₄), filtered andconcentrated by evaporation. The remaining residue is purified bychromatography (DCM/EtOH 85:15). 9 mg (0.023 mmol, corresponding to 42%of theory) of the product is obtained.

¹H-NMR (DMSO): 10.17 (s, 1H), 8.45 (s, 1H), 7.94 (m, 2H), 7.78 (m, 2H),4.49 (q, 2H), 3.98 (s, 1H), 3.07 (q, 2H), 1.40 (tr, 3H), 1.04 (tr, 3H).

MS: 385 (ES).

EXAMPLE 1.64 Production of(RS)—N-(ethoxycarbonyl)-S-(4-{[5-iodo-4-(prop-2-in-1-ylamino)pyrimidin-2-yl]amino}phenyl)-S-methylsulfoximide

400 mg (1.65 mmol) of(2-chloro-5-iodopyrimidin-4-yl)-prop-2-in-1-yl-amine and 630 mg (2.15mmol) of (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methyl sulfoximidein 7 ml of acetonitrile are mixed with 0.6 ml of a 4N solution of HCl indioxane and 1 ml of water. The batch is stirred for 24 hours at 50° C.The solvent is drawn off, and the remaining residue is purified bychromatography (DCM/EtOH 9:1). 279 mg (0.56 mmol, corresponding to 54%of theory) of the product is obtained.

¹H-NMR (DMSO): 10.19 (s, 1H), 8.30 (s, 1H), 8.05 (m, 2H), 7.81 (m, 2H),7.59 (br, 1H), 4.17 (d, 2H), 3.88 (q, 2H), 3.43 (s, 3H), 3.18 (br, 1H),1.10 (tr, 3H).

MS: 500 (ES).

EXAMPLE 1.65 Production of(RS)—N-(ethoxycarbonyl)-S-{4-[(4-{(R)-[1-(hydroxymethyl)-2-methylpropyl]amino}-5-iodopyrimidin-2-yl)amino]phenyl}-S-methylsulfoximide

¹H-NMR (DMSO): 9.81 (s, 1H), 8.22 (s, 1H), 7.98 (m, 2H), 7.78 (m, 2H),5.89 (d, 1H), 4.85 (tr, 1H), 4.04 (m, 1H), 3.92 (q, 2H), 3.65 (m, 1H),3.56 (m, 1H), 3.41 (s, 3H), 2.02 (m, 1H), 1.10 (tr, 3H), 0.95 (dd, 6H).

MS: 548 (ES)

EXAMPLE 1.66 Production of(RS)—S-{4-[(4-{(R)-[1-(hydroxymethyl)-2-methylpropyl]amino}-5-iodopyrimidin-2-yl)amino]phenyl}-S-methylsulfoximide

¹H-NMR (DMSO): 9.68 (s, 1H), 8.21 (s, 1H), 7.92 (m, 2H), 7.75 (m, 2H),5.87 (d, 1H), 4.86 (tr, 1H), 4.01 (m, 2H), 3.66 (m, 1H), 3.55 (m, 1H),3.01 (s, 3H), 2.02 (m, 1H), 0.94 (m, 6H).

EXAMPLE 1.67 Production of(RS)—S-[4-({5-bromo-4-[(1R,2R)-(2-hydroxy-1-methylpropyl)amino]pyrimidin-2-yl}amino)-2-fluorophenyl]-N-(ethoxycarbonyl)-S-methylsulfoximide

¹H-NMR (DMSO): 10.08 (s, 1H), 8.18 (s, 1H), 8.02 (m, 1H), 7.68 (m, 2H),6.27 (d, 1H), 5.03 (br, 1H), 4.08 (m, 1H), 3.88 (m, 2H), 3.79 (m, 1H),3.48 (s, 3H), 1.21 (d, 3H), 1.09 (m, 6H).

MS: 504 (ES).

EXAMPLE 1.68 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)-2-fluorophenyl]-N-(ethoxycarbonyl)-S-methylsulfoximide

¹H-NMR (DMSO): 10.12 (s, 1H), 8.17 (s, 1H), 8.02 (m, 1H), 7.73 (m, 1H),7.63 (m, 1H), 6.26 (d, 1H), 4.08 (m, 1H), 3.85 (m, 2H), 3.42 (s, 3H),1.11 (m, 12H).

MS: 518 (ES).

EXAMPLE 1.69 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]pyrimidin-2-yl}amino)-2-trifluoromethylphenyl]-N-(ethoxycarbonyl)-S-methylsulfoximide

¹H-NMR (DMSO): 10.21 (s, 1H), 8.65 (s, 1H), 8.19 (s, 1H), 8.05 (s, 2H),6.18 (d, 1H), 4.90 (br, 1H), 4.05 (m, 1H), 3.89 (q, 2H), 3.40 (s, 3H),1.12 (m, 12H).

MS: 568 (ES).

Substituents R¹, R², R³, R⁴, R⁵, Q, and m have the meaning that isindicated in general formula (I).

METHOD A EXAMPLE 2.0 Production of(RS)—S-(4-{[5-bromo-4-(isopropylamino)pyrimidin-2-yl]amino}phenyl)-S-methylsulfoximide

185 mg (0.50 mmol) of (RS)-5-bromo-N⁴-isopropyl-N²-[4-(methylsulfinyl)phenyl]-pyrimidine-2,4-diamine in 1 ml of DCM is mixed with 40mg (0.55 mmol) of sodium azide. The batch is slowly mixed with 0.13 mlof concentrated sulfuric acid at 0° C. and then heated to 45° C. After16 hours, the batch is cooled to room temperature, mixed with 2 ml of 1NNaOH solution and extracted from ethyl acetate. The combined organicphases are dried (Na₂SO₄), filtered and concentrated by evaporation. Theremaining residue is purified by chromatography (DCM/EtOH 9:1). 38 mg(0.10 mmol, corresponding to 20% of theory) of the product is obtained.

¹H-NMR (DMSO): 9.70 (s, 1H), 8.08 (s, 1H), 7.90 (d, 2H), 7.77 (d, 2H),6.62 (d, 1H), 4.35 (m, 1H), 3.99 (s, 1H), 3.03 (s, 3H), 1.29 (d, 6H).

MS: 384 (ES).

METHOD B EXAMPLE 2.1 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1-methylethyl)amino]pyrimidin-2-yl}amino)phenyl]-S-methyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide

50 mg (0.13 mmol) of(R)-2-[5-bromo-2-{(RS)-4-methylsulfinyl-phenylamino}-pyrimidin-4-ylamino]-propan-1-olin 3 ml of acetonitrile is mixed with a spatula tip full ofCuPF₆[CH₃CN]₄ (about 0.05 equivalent) and stirred for 30 minutes at roomtemperature. The mixture is cooled in an ice bath, mixed with 55 mg(0.13 mmol) of[N-(2-(trimethylsilyl)ethanesulfonyl)imino]phenyliodinane, and stirredfor 4 hours at room temperature. It is cooled again in the ice bath,mixed with a spatula tip full of CuPF₆[CH₃CN]₄ and with 22 mg (0.06mmol) of [N-(2-(trimethylsilyl)ethanesulfonyl)-imino]phenyliodinane andstirred for another 3 hours at room temperature. The mixture isevaporated to the dry state, and the remaining residue is purified bychromatography. 20 mg of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1-methylethyl)amino]pyrimidin-2-yl}amino)phenyl]-S-methyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximidewith a melting point of 194-197° C. is obtained.

¹H-NMR (DMSO): 9.92 (s, 1H), 8.14 (s, 1H), 8.02 (d, 2H), 7.87 (d, 2H),6.48 (d, 1H), 4.90 (t, 1H), 4.27 (m, 1H), 3.53 (s, 3H), 3.52 (m, 2H),2.95 (m, 2H), 1.22 (d, 3H), 0.95 (m, 2H), 0.01 (s, 9H).

MS: 564/566 (100%, ES).

Produced in a way that is similar to the above-mentioned methods A and Bof Process Variant 2 are the following compounds:

EXAMPLE 1.0 Production of(RS)—S-[4-({5-bromo-4-[(R)-(2-hydroxy-1-methylethyl)amino]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

After the Ses-protective group is cleaved with tetrabutylammoniumfluoride analogously to Example 1.6 (as described in Tetrahedron Lett.2002, 43, 2751), 10 mg (0.02 mmol, corresponding to 70% of theory) ofthe product is obtained.

EXAMPLE 2.2 Production of(RS)—S-(4-{[5-bromo-4-(phenylamino)pyrimidin-2-yl]amino}phenyl)-S-methyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide

¹H-NMR (DMSO): 9.98 (s, 1H), 8.83 (s, 1H), 8.32 (s, 1H), 7.88 (d, 2H),7.71 (d, 2H), 7.59 (d, 2H), 7.44 (t, 2H), 7.23 (t, 1H), 3.53 (s, 3H),2.86-3.03 (m, 2H), 0.82-1.01 (m, 2H), 0.00 (s, 9H).

MS: 582/584 (100%, ES).

EXAMPLE 2.3 Production of(RS)—S-(4-{[5-bromo-4-(phenylamino)pyrimidin-2-yl]amino}phenyl)-S-methylsulfoximide

¹H-NMR (DMSO): 9.82 (s, 1H), 8.79 (s, 1H), 8.30 (s, 1H), 7.78 (d, 2H),7.65 (d, 2H), 7.60 (d, 2H), 7.42 (t, 2H), 7.23 (t, 1H), 3.96 (s, 1H),3.00 (s, 3H).

MS: 418/420 (20%, ES).

EXAMPLE 2.4 Production of(RS)—S-[4-({4-[(2-fluoro-5-methylphenyl)amino]-pyrimidin-2-yl}amino)phenyl]-S-methyl-N-[2-(trimethylsilyl)ethylsulfonyl]-sulfoximide

¹H-NMR (DMSO): 9.85 (s, 1H), 9.22 (s, 1H), 7.98 (d, 2H), 7.88 (d, 1H),7.76 (d, 2H), 7.63 (d, 1H), 7.21 (m, 1H), 7.02 (m, 1H), 6.40 (m, 1H),3.53 (s, 3H), 2.81-2.90 (m, 2H), 0.87-1.00 (m, 2H), 0.00 (s, 9H).

MS: 536 (100%, ES).

EXAMPLE 2.5 Production of(RS)—S-[4-({4-[(2-fluoro-5-methylphenyl)amino]-pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 9.65 (s, 1H), 9.18 (s, 1H), 8.09 (d, 1H), 7.87 (d, 2H),7.69 (d, 2H), 7.65 (d, 1H), 7.19 (m, 1H), 7.02 (m, 1H), 6.37 (m, 1H),3.02 (s, 3H).

MS: 372 (10%, ES).

The substituents R¹, R², R³, R⁴, R⁵, Q, and m have the meaning that isindicated in general formula (I). Y has the meaning of halogen.

EXAMPLE 3.0 Production of(RS)—S-[4-({5-bromo-4-[(RS)-(1-hydroxymethyl-propyl)sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

362 mg of(RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methylsulfoximide is dissolved in 1.5 ml of dimethylformamide, mixed with 0.5ml of triethylamine and 320 mg of (RS)-2-mercapto-butan-1-ol and stirredfor 18 hours at room temperature. The mixture is evaporated to the drystate in a vacuum and purified by flash chromatography(dichloromethane/ethanol). 255 mg of the product with a melting point of175-180° C. is obtained.

¹H-NMR (DMSO): 10.18 (s, 1H), 8.39 (s, 1H), 7.91 (d, 2H), 7.83 (d, 2H),5.13 (t, 1H), 4.05 (s, 1H), 4.00 (m, 1H), 3.74 (m, 1H), 3.63 (m, 1H),3.03 (s, 3H), 1.93 (m, 1H), 1.69 (m, 1H), 1.00 (t, 3H).

MS: 431/433 (95/100%, ES).

Produced in a similar way are the following examples:

EXAMPLE 3.1 Production of(RS)—S-[4-({5-bromo-4-[(RS)-(1-methyl-propyl)-sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

Melting point: 175-183° C.

¹H-NMR (DMSO): 10.19 (s, 1H), 8.40 (s, 1H), 7.95 (d, 2H), 7.85 (d, 2H),4.04 (s, 1H), 3.97 (m, 1H), 3.03 (s, 3H), 1.76 (m, 2H), 1.42 (d, 2H),1.01 (t, 3H).

MS: 415/417 (90/100%, ES).

EXAMPLE 3.2 Production of(RS)—S-[4-({5-bromo-4-[(RS)-(1-methyl-2-oxo-propyl)-sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 10.18 (s, 1H), 8.44 (s, 1H), 7.87 (s, 4H), 4.82 (q, 1H),3.06 (s, 3H), 2.26 (s, 3H), 1.52 (d, 3H).

MS: 429/431 (90/100%, ES).

EXAMPLE 3.3 Production of(RS)—S-[4-({4-[(RS)-(1-acetylpropyl)sulfanyl]-5-bromopyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 10.16 (s, 1H), 8.44 (s, 1H), 7.86 (s, 4H), 4.79 (t, 1H),3.04 (s, 3H), 2.25 (s, 3H), 2.04 (m, 1H), 1.89 (m, 1H), 1.18 (t, 1.5H),0.96 (t, 1.5H).

MS: 443/445 (90/100%, ES).

EXAMPLE 3.4 Production of(RS)—S-[4-({5-bromo-4-[(RS)-(2-hydroxy-propyl)sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 10.17 (s, 1H), 8.39 (s, 1H), 7.90 (d, 2H), 7.84 (d, 2H),5.04 (d, 1H), 4.04 (s, 1H), 3.93 (m, 1H), 3.26 (d, 1H), 3.03 (s, 3H),1.21 (d, 3H).

MS: 417/419 (90/100%, ES).

EXAMPLE 3.5 Production of(RS)—S-[4-({5-bromo-4-[(RS,RS)-(2-hydroxy-1-methylpropyl)sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 10.17 (s, 1H), 8.38 (s, 1H), 7.93-7.81 (m, 4H), 5.13+5.06(d, 1H), 4.06 (m, 1H), 4.04 (s, 1H), 3.95 (m, 1H), 3.03 (s, 3H),1.42+1.36 (d, 3H), 1.18 (m, 3H).

MS: 431/433 (94/100%, ES).

EXAMPLE 3.6 Production of(RS)—S-[4-({5-bromo-4-[(RS,RS)-(1-ethyl-2-hydroxypropyl)sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

is obtained by reaction of(RS)—S-[4-({4-[(RS)-(1-acetylpropyl)sulfanyl]-5-bromopyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide with 1 equivalent of sodium borohydride intetrahydrofuran/methanol (1:1).

Melting point: 192-194° C.

¹H-NMR (DMSO): 10.14 (s, 1H), 8.38 (s, 1H), 7.90 (d, 2H), 7.83 (d, 2H),5.06+4.98 (d, 1H), 4.08 (s, 1H), 4.00 (m, 2H), 3.03 (s, 3H), 1.93 (m,1H), 1.66 (m, 1H), 1.16 (d, 3H), 0.99 (t, 3H).

MS: 445/447 (96/100%, ES).

EXAMPLE 3.7 Production of(RS)—S-[4-({5-bromo-4-[(RS)-(2-hydroxy-1,2-dimethylpropyl)sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

is obtained by reaction of(RS)—S-[4-({5-bromo-4-[(RS)-(1-methyl-2-oxo-propyl)-sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide with 6 equivalents of methylmagnesium bromide intetrahydrofuran.

Melting point: 201-202° C.

¹H-NMR (DMSO): 10.18 (s, 1H), 8.38 (s, 1H), 7.92 (d, 2H), 7.83 (d, 2H),4.89 (s, 1H), 4.09 (m, 1H), 4.05 (s, 1H), 3.03 (s, 3H), 1.43 (d, 3H),1.27 (s, 6H).

MS: 445/447 (93/100%, ES).

EXAMPLE 3.8 Production of(RS)—S-[4-({5-bromo-4-[(RS)-(1-ethyl-2-hydroxy-2-methylpropyl)sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

is obtained by reaction of(RS)—S-[4-({4-[(RS)-(1-acetylpropyl)sulfanyl]-5-bromopyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide with 6 equivalents of methylmagnesium bromide intetrahydrofuran.

Melting point: 218° C. (decomposition)

¹H-NMR (DMSO): 10.17 (s, 1H), 8.38 (s, 1H), 7.92 (d, 2H), 7.83 (d, 2H),4.78 (s, 1H), 4.12 (dd, 1H), 4.05 (s, 1H), 3.03 (s, 3H), 2.10 (m, 1H),1.48 (m, 1H), 1.24 (s, 6H), 0.95 (dd, 3H).

MS: 459/461 (93/100%, ES).

EXAMPLE 3.9 Production of(RS)—S-[4-({5-bromo-4-[(2-hydroxy-2-methyl-propyl)-sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

is obtained by reaction of(RS)—S-[4-({5-bromo-4-[(4-methoxycarbonylmethyl)-sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide with 6 equivalents of methylmagnesium bromide intetrahydrofuran.

¹H-NMR (DMSO): 10.17 (s, 1H), 8.39 (s, 1H), 7.92 (d, 2H), 7.83 (d, 2H),4.84 (s, 1H), 4.05 (s, 1H), 3.41 (s, 2H), 3.03 (s, 3H), 1.26 (s, 6H).

MS: 431/433 (94/100%, ES).

EXAMPLE 3.10 Production of(RS)—S-[4-({5-bromo-4-[(RS)-(2-hydroxy-1-methyl-ethyl)sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

Melting point: 218-220° C.

¹H-NMR (DMSO): 10.19 (s, 1H), 8.40 (s, 1H), 7.92 (d, 2H), 7.84 (d, 2H),5.18 (t, 1H), 4.07 (m, 2H), 3.69 (m, 1H), 3.61 (m, 1H), 3.04 (s, 3H),1.42 (d, 3H).

MS: 417/419 (92/100%, ES).

EXAMPLE 3.11 Production of(RS)—S-[4-({5-bromo-4-[(4-methoxycarbonylmethyl)-sulfanyl]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide

¹H-NMR (DMSO): 10.22 (s, 1H), 8.44 (s, 1H), 7.82 (s, 4H), 4.22 (s, 2H),4.16 (s (br), 1H), 3.58 (s, 3H), 3.05 (s, 3H).

MS: 431/433 (91/100%, ES).

EXAMPLES 3.12/3.13 Production and Separation into the Diastereomers of(RS)—S-[4-({5-bromo-4-[(1R,2R)-2-hydroxy-1-methylpropoxy]pyrimidin-2-yl}amino)phenyl]-S-methylsulfoximide (Example 1.4)

A solution of 674 mg (7.5 mmol) of (R,R)-(−)-2,3-butanediol in 6 ml ofDMSO is mixed while being cooled with water in portions with 330 mg ofsodium hydride (55-60%), and then stirred for 45 minutes at roomtemperature. The batch is mixed with 196 mg (0.54 mmol) of(RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methylsulfoximide in 0.5 ml of DMSO and stirred overnight. It is mixed againwith 191 mg (0.53 mmol) of(RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methylsulfoximide in 0.5 ml of DMSO and stirred for another two hours.Finally, it is mixed with 190 mg of(RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methylsulfoximide (0.53 mmol) in 0.5 ml of DMSO and stirred for one hour. Thebatch is added to ice water and extracted from ethyl acetate (4×). Thecombined organic phases are washed with NaCl solution, filtered througha Whatman filter and concentrated by evaporation. The remaining residueis purified by chromatography (DCM/EtOH 9:1). 166 mg (0.41 mmol,corresponding to 25% of theory) of the product is obtained.

The analytical data are consistent with those from the preparationaccording to Process Variant 1.

The diastereomer mixture is cleaved into the diastereomers by means ofpreparatory HPLC:

Column: Chiracel OJ 20μ

Length×ID: 290×50.8 mm

Eluants: A: Hexane, B: Ethanol

Flow: 80 ml/min

Gradient: Isocratic 15% B

Detector: UV 300 nm

Temperature: Room temperature

RT in min: 32.8: Diastereomer 1 (Example 3.12)

-   -   39.2: Diastereomer 2 (Example 3.13)

Production of the Intermediate Products a) Production of(RS)—S-(4-aminophenyl)-S-methyl sulfoximide

A solution of 2.45 g (12.2 mmol) of (RS)—S-(4-nitrophenyl)-S-methylsulfoximide in 150 ml of ethanol is hydrogenated at room temperaturewith use of 0.80 g of Pd/C (10%×50% H₂O) under a hydrogen atmosphere atnormal pressure over 4 hours. The hydrogen absorption is 920 ml. Thebatch is filtered and concentrated by evaporation. The residue that isobtained is digested with diisopropyl ether. 1.90 g (11.2 mmol,corresponding to 92% of theory) is obtained.

¹H-NMR (DMSO): 7.53 (d, 2H), 6.64 (d, 2H), 5.91 (s, 2H), 3.68 (s, 1H),2.93 (s, 3H).

ES: 171 (ES).

b) Production of (RS)—S-(4-nitrophenyl)-S-methyl sulfoximide

1.56 g (8.5 mmol) of 1-(methylsulfinyl)-4-nitrobenzene in 20 ml of DCMis mixed with 0.70 g (9.5 mmol) of sodium azide. The batch is slowlymixed at 0° C. with 2.3 ml of concentrated sulfuric acid and then heatedto 45° C. After 16 hours, the batch is cooled to room temperature, mixedwith water and extracted from DCM. The aqueous phase is set at pH 11with 15% NaOH solution and extracted from DCM. The combined organicphases are dried (Na₂SO₄), filtered and concentrated by evaporation.1.08 g (5.4 mmol, corresponding to 63% of theory) of the product isobtained.

¹H-NMR (DMSO): 8.43 (d, 2H), 8.17 (d, 2H), 4.62 (s, 1H), 3.18 (s, 3H).

ES: 201 (ES).

c) Production of 1-(Methylsulfinyl)-4-nitrobenzene

A solution of 16.0 g (95 mmol) of 1-methylsulfanyl-4-nitro-benzene in400 ml of DCM is mixed at room temperature with 24.6 g (100 mmol) of3-chloroperoxybenzoic acid (about 70%). After 1 hour, the batch isdiluted with DCM and washed with saturated NaHCO₃ solution. The organicphase is dried (Na₂SO₄), filtered and concentrated by evaporation. Theremaining residue is purified by chromatography (DCM/EtOH 8:2). 7.6 g(41 mmol, corresponding to 43% of theory) of the product is obtained.

¹H-NMR (DMSO): 8.41 (d, 2H), 7.97 (d, 2H), 2.86 (s, 3H).

ES: 186 (ES).

d) Production of (RS)—S-(3-aminophenyl)-S-methyl sulfoximide

A solution of 200 mg (1.00 mmol) of(RS)—S-methyl-S-(3-nitrophenyl)sulfoximide in 20 ml of THF is mixed atroom temperature with 8 ml of an approximately 10% solution of Ti(III)Clin 20-30% hydrochloric acid. After 3 hours, another 2 ml of theapproximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid isadded and stirred overnight at room temperature. The batch is made basicwith 1N NaOH solution and mixed with ethyl acetate. It is filtered, andthe filter cakes are washed with ethyl acetate/MeOH (3:2). The organicsolvent is drawn off in a rotary evaporator, and the residue isextracted from ethyl acetate. The combined organic phases are dried(Na₂SO₄), filtered and concentrated by evaporation. The residue that isobtained is purified by chromatography (DCM/EtOH 95:5). 82 mg (0.48mmol, corresponding to 48% of theory) of the product is obtained.

¹H-NMR (DMSO): 7.19 (m, 1H), 7.11 (m, 1H), 7.00 (m, 1H), 6.75 (m, 1H),5.56 (s, 2H), 3.96 (s, 1H), 2.98 (s, 3H).

ES: 171 (ES).

e) Production of (RS)—S-(3-aminophenyl)-S-methyl-N-nitrosulfoximide

A solution of 100 mg (0.41 mmol) of(RS)—S-methyl-N-nitro-S-(3-nitrophenyl)sulfoximide in 8 ml of THF ismixed at room temperature with 3.1 ml of an approximately 10% solutionof Ti(III)Cl in 20-30% hydrochloric acid. After 1 hour, another 1.0 mlof the approximately 10% solution of Ti(III)Cl in 20-30% hydrochloricacid is added, and it is stirred for another 45 minutes at roomtemperature. The batch is made basic with 1N NaOH solution and extractedwith ethyl acetate. The combined organic phases are dried (Na₂SO₄),filtered and concentrated by evaporation. The residue that is obtainedis purified by chromatography (DCM/EtOH 95:5). 40 mg (0.19 mmol,corresponding to 45% of theory) of the product is obtained.

¹H-NMR (DMSO): 7.33 (m, 1H), 7.13 (m, 1H), 7.03 (m, 1H), 6.90 (m, 1H),5.88 (s, 2H), 3.59 (s, 3H).

ES: 216 (ES).

f) Production of (RS)—S-methyl-N-nitro-S-(3-nitrophenyl)sulfoximide (A)and (RS)—S-methyl-S-(3-nitrophenyl)sulfoximide (B)

1.0 g (6.45 mmol) of (RS)—S-phenyl-S-methyl sulfoximide is carefullymixed with 3 ml of concentrated sulfuric acid. While being stirred at 0°C., the batch is carefully mixed drop by drop with 1 ml of fuming nitricacid and slowly heated overnight to room temperature. The reactionsolution is carefully added to ice-cooled 1N NaOH solution. The basicbatch is extracted from ethyl acetate. The combined organic phases aredried (Na₂SO₄), filtered and concentrated by evaporation. The residuethat is obtained is mixed with 15 ml of MeOH. The precipitate that isformed is suctioned off and washed with diisopropyl ether. After drying,485 mg (1.98 mmol, corresponding to 31% of theory) of product A isobtained. The filtrate is spun in, and the precipitate that is formed ispurified by chromatography (DCM/EtOH 97:3). 200 mg (1.00 mmol,corresponding to 16% of theory) of product B is obtained.

(A):

¹H-NMR (DMSO): 8.79 (m, 1H), 8.64 (m, 1H), 8.49 (m, 1H), 8.05 (m, 1H),3.88 (s, 3H).

(B):

¹H-NMR (DMSO): 8.65 (m, 1H), 8.48 (m, 1H), 8.35 (m, 1H), 7.90 (m, 1H),4.62 (s, 1H), 3.17 (s, 3H).

MS: 201 (ES).

g) Production of5-bromo-N⁴-isopropyl-N²-[4-(methylsulfinyl)phenyl)-pyrimidine-2,4-diamine

1.77 g (4.6 mmol) of5-bromo-N⁴-isopropyl-N²-[4-(methylsulfanyl)phenyl)-pyrimidine-2,4-diaminehydrochloride is taken up in 40 ml of DCM and mixed with 1.73 g (5.5mmol) of 3-chloroperoxybenzoic acid (55%). The batch is stirred for 90minutes at room temperature and then diluted with DCM. It is washed withsaturated NaHCO₃ solution and saturated NaCl solution. The organic phaseis dried (Na₂SO₄), filtered and concentrated by evaporation. Theremaining residue is purified by chromatography (DCM/EtOH 9:1). 553 mg(1.5 mmol, corresponding to 33% of theory) of the product is obtained.

¹H-NMR (DMSO): 9.55 (s, 1H), 8.08 (s, 1H), 7.90 (d, 2H), 7.53 (d, 2H),6.53 (d, 1H), 4.35 (m, 1H), 2.70 (s, 3H), 1.25 (d, 6H).

MS: 369 (ES).

h) Production of5-Bromo-N⁴-isopropyl-N²-[4-(methylsulfanyl)phenyl)-pyrimidine-2,4-diamine

A solution of 4.08 g (16.3 mmol) of(5-bromo-2-chloro-pyrimidin-4-yl)-isopropyl-amine in 20 ml ofacetonitrile is mixed at room temperature with a solution of 2 ml (16.3mmol) of 4-methylsulfanyl-phenylamine in 10 ml of acetonitrile. Thebatch is mixed with 4.1 ml of a 4 molar solution of hydrochloric acid indioxane and 4.1 ml of water, and then it is stirred under reflux for 16hours. After cooling, the precipitate that is formed is suctioned off,washed with water and dried. 4.94 g (12.7 mmol, corresponding to 78% oftheory) of the product is obtained in the form of hydrochloride.

¹H-NMR (DMSO): 10.39 (s, 1H), 8.18 (s, 1H), 7.88 (br, 1H), 7.49 (d, 2H),7.29 (d, 2H), 4.30 (m, 1H), 2.5 (s, 3H), 1.21 (d, 6H).

MS: 353 (ES).

Additional Intermediate Products

Substituents R¹ and R² have the meaning that is indicated in generalformula (I).

i) Production of(R)-2-[(5-Bromo-2-chloropyrimidin-4-yl)amino]propan-1-ol

A solution of 22.8 g (100 mmol) of 5-bromo-2,4-dichloropyrimidine in 100ml of acetonitrile is mixed at 0° C. first with 17.0 ml (125 mmol) oftriethylamine and then with 9.4 g (125 mmol) of D-alaninol. The batch isstirred overnight at room temperature. The precipitate that is formed issuctioned off, washed with water, and completely dried. 21.5 g (81 mmol,corresponding to 81% of theory) of the product is obtained.

¹H-NMR (DMSO): 8.21 (s, 1H), 7.05 (d, 1H), 4.86 (t, 1H), 4.16 (m, 1H),3.41 (m, 2H), 1.17 (d, 3H).

j) Production of(2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)oxy]-butan-2-ol

A solution of 1.35 g (15.0 mmol) of (R,R)-(−)-2,3-butanediol in 50 ml ofTHF is mixed at 0° C. in portions with 480 mg (11.0 mmol) of sodiumhydride (55% dispersion) and then stirred for 10 minutes at roomtemperature. The solution that is produced is added at 0° C. to 2.27 g(10.0 mmol) of 5-bromo-2,4-dichloropyrimidine in 25 ml of THF. The batchis slowly heated to room temperature and stirred for 12 hours. Thesolvent is drawn off, and the residue that is obtained is purified bychromatography (hexane/ethyl acetate 1:1). 2.29 g (8.1 mmol,corresponding to 81% of theory) of the product is obtained.

¹H-NMR (DMSO): 8.44 (s, 1H), 5.18 (q, 1H), 3.96 (q, 1H), 2.02 (d, 1H),1.4 (d, 3H), 1.28 (d, 3H).

MS: 281 (ES).

k) Production of(R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol

An ice-cooled solution of 2.95 g (10.0 mmol) ofmethyl-N-(5-bromo-2-chloropyrimidin-4-yl)-D-alaninate in 150 ml of THFis mixed drop by drop with 30 ml (90 mmol) of a 3 molar solution ofmethylmagnesium bromide in diethyl ether. After 2.5 hours at roomtemperature, the batch is mixed with 30 ml of saturated ammoniumchloride solution. It is diluted with water and extracted from ethylacetate (3×). The combined organic phases are dried (Na₂SO₄), filteredand concentrated by evaporation. The remaining residue is purified bychromatography (hexane/ethyl acetate: 4:1-1:1). 2.81 g (9.5 mmol,corresponding to 95% of theory) of the product is obtained.

¹H-NMR (CDCl₃): 8.1 (s, 1H), 5.9 (d, 1H), 4.2 (m, 1H), 1.8 (br, 1H), 1.2(m, 9H).

ka) Production of methyl-N-(5-bromo-2-chloropyrimidin-4-yl)-D-alaninate

22.8 g (100 mmol) of 5-bromo-2,4-dichloropyrimidine and 14.0 g (100mmol) of D-alanic acid methyl ester hydrochloride are dissolved in 300ml of THF and 75 ml of DMF. The ice-cooled batch is mixed with 33.5 ml(240 mmol) of triethylamine and then slowly heated to room temperature.After 48 hours, the solvent is drawn off in a rotary evaporator, and theremaining residue is purified by chromatography (hexane/ethyl acetate:4:1-2:1). 25.5 g (86.1 mmol, corresponding to 86% of theory) of theproduct is obtained.

¹H-NMR (CDCl₃): 8.2 (s, 1H), 6.1 (d, 1H), 4.8 (m, 1H), 3.8 (s, 3H), 1.6(d, 3H).

l) Production of(2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]butan-2-ol

32.7 g (159 mmol) of copper(I)bromide dimethyl sulfide complex isintroduced under nitrogen atmosphere into 1000 ml of diethyl ether andcooled to −78° C. Over a period of about 25 minutes, 200 ml of a 1.6molar solution of methyllithium in diethyl ether is added in drops, andthen the cooling bath is removed. The batch is stirred for 40 minutes,and the temperature increases to −35° C. It is cooled to −55° C., and18.9 g (71.5 mmol) of(R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propanal is added over aperiod of 20 minutes. It is stirred for 6 hours at −55° C., then thecooling bath is filled with dry ice again, covered with aluminum foil,and the batch is stirred overnight. 200 ml of a saturated ammoniumchloride solution is added in drops, and the batch is heated to roomtemperature. It is diluted with 500 ml of diethyl ether, the organicphase is separated, and the aqueous phase is extracted with diethylether. The combined organic phases are washed with saturated ammoniumchloride solution and saturated NaCl solution, dried (Na₂SO₄), filteredand concentrated by evaporation. The remaining residue is purified bychromatography (hexane/ethyl acetate: 4:1-1:1). 8.4 g (30.0 mmol,corresponding to 42% of theory) of the product is obtained.

¹H-NMR (CDCl₃): 8.1 (s, 1H), 5.8 (d, 1H), 4.2 (m, 1H), 3.9 (m, 1H), 2.0(d, 1H), 1.3 (d, 3H), 1.2 (d, 3H).

HPLC Analysis:

Column: Chiralpak AD-H 5μ

Length×ID: 150×4.6 mm

Eluants: A=Hexane, C=Ethanol

Flow: 1.0 ml/min

Gradient: Isocratic 5% C

Detector: UV 254 nm

Temperature: 25° C.

RT in min: 6.04

la) Production of (R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propanal

A solution of 40.0 g (135.8 mmol) ofmethyl-N-(5-bromo-2-chloropyrimidin-4-yl)-D-alaninate in 800 ml oftoluene is mixed at −78° C. with 310 ml of a 1.2 molar solution ofdiisobutyl aluminum hydride. After 30 minutes, it is carefully quenchedwith methanol. The batch is heated to room temperature and diluted with1000 ml of tert-butyl methyl ether. It is washed successively with 1NHCl (3×100 ml), saturated sodium bicarbonate solution (3×) and saturatedNaCl solution (3×). The organic phase is dried (MgSO₄), filtered andconcentrated by evaporation. The remaining residue is purified bychromatography (hexane/ethyl acetate: 4:1-1:1). 22.5 g (83.9 mmol,corresponding to 62% of theory) of the product is obtained.

¹H-NMR (CDCl₃): 9.6 (s, 1H), 8.2 (s, 1H), 6.3 (d, 1H), 4.8 (m, 1H), 1.5(d, 3H).

lb) Production of(2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-4-methoxybutan-2-ol

311 mg (2.6 mmol) of (2R,3R)-3-amino-4-methoxy-butan-2-ol hydrochloride(production according to A. I. Meyers, D. Hoyer, Tet. Lett. 1985, 26,4687) in 2 ml of acetonitrile is mixed with 0.28 ml of triethylamine andshaken. It is filtered, and the filter cakes are washed with 2 ml ofacetonitrile. The filtrate is added in drops to a solution of 455 mg(2.0 mmol) of 5-bromo-2,4dichloro-pyrimidine in 26 ml of acetonitrile at−30° C. By removal of the cooling bath, it is slowly heated to roomtemperature while being stirred. After 16 hours, the solvent is drawnoff in a rotary evaporator, and the remaining residue is purified bychromatography (hexane/ethyl acetate: 4:1-1:1). 509 mg (1.6 mmol,corresponding to 80% of theory) of the product is obtained.

¹H-NMR (CDCl₃): 8.1 (s, 1H), 6.3 (d, 1H), 4.3 (m, 1H), 4.2 (m, 1H), 3.8(d, 2H), 3.4 (s, 3H), 3.1 (d, 1H), 1.2 (d, 3H).

lc) Production of 5-bromo-2-chloropyrimidin-4-ol

50.5 g of 5-bromo-2,4-dichloropyrimidine is mixed with 133 ml of 2Nsodium hydroxide solution and stirred for 50 minutes at 45-50° C. Aftercooling, it is acidified with 21 ml of concentrated hydrochloric acidwhile being cooled with ice. The precipitate is suctioned off, washedwith water and a little methylene chloride and dried at 25-35° C. 17.12g (36.9% of theory) of the product with a melting point of 136-145° C.(decomposition) is obtained.

Produced in a way that is similar to the above-described processvariants in each case are also the compounds below:

Example m ma mb MS 250 (CI) 293 (EI) 341 (EI)

n) Production of 5-bromo-2-[4-(methylsulfanyl)phenylamino]pyrimidin-4-ol

9.8 g of 5-bromo-2-chloropyrimidin-4-ol is suspended in 200 ml ofacetonitrile. After 7.2 g of 4-methylsulfanyl-phenylamine is added, 12ml of a 4N solution of HCl in dioxane is added in drops while beingstirred vigorously. After drop-by-drop addition of 5 ml of water, themixture is stirred for 3 hours at 78° C. and for 2 days at roomtemperature. The mixture is cooled in an ice bath and suctioned off. Thefilter cake is washed twice with acetonitrile and dried. 15.2 g (92.7%of theory) of the product with a melting point of 238° C.(decomposition) is obtained.

o) Production of(RS)-5-bromo-2-[4-(methylsulfinyl)phenylamino]pyrimidin-4-ol

11 g of 5-bromo-2-[4-(methylsulfanyl)phenylamino]pyrimidin-4-ol issuspended in 110 ml of glacial acetic acid. While being cooled with icewater, 4.6 ml of a 30% solution of hydrogen superoxide is added indrops. The mixture is stirred for 18 hours at room temperature and thensuctioned off. The filter cake is washed twice with water and once withethanol and dried at 60° C. in a vacuum. 8.75 g (75.7% of theory) of theproduct with a melting point of 240° C. (decomposition) is obtained.

p) Production of(RS)—S-{4-[(5-bromo-4-hydroxypyrimidin-2-yl)amino]phenyl}-S-methylsulfoximide

324 mg of (RS)-5-bromo-2-[4-(methylsulfinyl)phenylamino]pyrimidin-4-oland 128 mg of sodium azide are suspended in 6 ml of methylene chlorideand mixed drop by drop with 0.3 ml of concentrated sulfuric acid whilebeing cooled with ice. The mixture is stirred for 36 hours at 40° C. Theorganic phase is decanted off, and the residue is stirred with icewater. The solid is suctioned off, washed twice with water and once withethanol and dried. 266 mg (78.2% of theory) of the product with amelting point of 230° C. (decomposition) is obtained.

q) Production of(RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methylsulfoximide

255 mg of(RS)—S-{4-[(5-bromo-4-hydroxypyrimidin-2-yl)amino]phenyl}-S-methylsulfoximide is suspended in 1.5 ml of phosphorus oxychloride and stirredfor 3 hours at 106° C. and for 16 hours at room temperature. The mixtureis poured into ice water, made alkaline with 25% ammonia solution whilebeing cooled intensely (temperature <5° C.) and stirred for 1 hour in anice bath. The precipitate is suctioned off, washed with water and driedat 60° C. 220 mg (81.8% of theory) of the product with a melting pointof 170-173° C. is obtained.

r) Production of(RS)—S-(4-aminophenyl)-S-cyclopropyl-N-[2-(trimethylsilyl)-ethylsulfonyl]sulfoximide

320 mg of(RS)—S-cyclopropyl-S-(4-nitrophenyl)-N-[2-(trimethylsilyl)ethyl-sulfonyl]sulfoximideis dissolved in 5 ml of tetrahydrofuran. While being cooled with ice,7.2 ml of an approximately 10% by weight solution of titanium(III)chloride in 20-30% by weight of hydrochloric acid is added in drops. Thesolution is stirred for 16 hours at room temperature and poured ontoice. The pH is set at 8-9 with 15% sodium hydroxide solution. Afterethyl acetate is added, the mixture is vigorously stirred. Theprecipitate is suctioned off and washed with 100 ml of ethyl acetate.The filtrates are combined, dried and concentrated by evaporation. Afterpurification by flash chromatography, 215 mg of(RS)—S-(4-aminophenyl)-S-cyclopropyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximideis obtained.

Melting point: 137-138° C.

Produced in a similar way are also(RS)—S-(4-aminophenyl)-S-cyclopropyl-methyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide(melting point: 138-140° C.) and(RS)—S-(4-aminophenyl)-S-cyclopentyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide(melting point: 146-147° C.).

s) Production of(RS)—S-cyclopropyl-S-(4-nitrophenyl)-N-[2-(trimethylsilyl)ethyl-sulfonyl]sulfoximide

260 mg of (RS)-1-(cyclopropylsulfinyl)-4-nitrobenzene is dissolved in 10ml of acetonitrile, mixed with 100 mg oftetrakis-(acetonitrile)-copper(I)-hexafluorophosphate and stirred for 45minutes at room temperature. The solution is cooled in an ice bath andmixed with 613 mg of[N-(2-(trimethylsilyl)ethanosulfonyl)imino]phenyliodinane (PhI═NSes: J.Org. Chem., 64(14), 5304-5307 (1999)). After 30 minutes of stirring at0° C., another 232 mg of PhI═NSes is added. After 2 hours of stirring at0° C., another 60 mg of PhI═NSes and 10 mg oftetrakis-(acetonitrile)-copper(I)-hexafluorophosphate is added. After 30minutes of stirring at 0° C., the mixture is concentrated byevaporation. The oily residue is mixed with hexane, whereby the productcrystallizes. The solution is decanted off, and the solid is purified byflash chromatography (hexane/ethyl acetate). 325 mg of(RS)—S-cyclopropyl-S-(4-nitrophenyl)-N-[2-(trimethylsilyl)ethylsulfonyl]-sulfoximideis obtained.

Melting point: 111-114° C.

t) Production of (RS)-1-(cyclopropylsulfinyl)-4-nitrobenzene

350 mg of 1-(cyclopropylsulfanyl)-4-nitrobenzene is dissolved in 5 ml ofacetonitrile and mixed with 10 mg of iron(III)-chloride hexahydrate.After 10 minutes of stirring at room temperature, 450 mg of periodicacid is added thereto while being cooled. The mixture is stirred for 30minutes at room temperature, cooled in an ice bath and mixed drop bydrop with semi-saturated sodium disulfite solution. It is diluted withmethylene chloride, washed with water, sodium bicarbonate solution andsaturated sodium chloride solution, and concentrated by evaporation.After purification by flash chromatography, 270 mg of(RS)-1-(cyclopropylsulfinyl)-4-nitrobenzene is obtained.

Melting point: 104-106° C.

Produced in a similar way are:

ta) Production of (RS)-1-(ethylsulfinyl)-4-nitrobenzene

¹H-NMR (DMSO): 8.39 (m, 2H), 7.91 (m, 2H), 3.18 (m, 1H), 2.88 (m, 1H),1.06 (tr, 3H).

tb) Production of (RS)-2-[(4-nitrophenyl)sulfinyl]ethanol

¹H-NMR (DMSO): 8.41 (m, 2H), 7.93 (m, 2H), 5.13 (tr, 1H), 3.84 (m, 1H),3.78 (m, 1H), 3.16 (m, 1H), 2.95 (m, 1H).

MS: 216 (ES).

tc) Production of (RS)-1-(isopropylsulfinyl)-4-nitrobenzene

¹H-NMR (DMSO): 8.39 (m, 2H), 7.88 (m, 2H), 3.10 (m, 1H), 1.25 (d, 3H),0.88 (d, 3H).

td) Production of (RS)-2-methyl-1-(methylsulfinyl)-4-nitrobenzene

¹H-NMR (DMSO): 8.31 (m, 1H), 8.19 (m, 1H), 8.04 (m, 1H), 2.78 (s, 3H),2.45 (s, 3H).

MS: 200 (ES).

te) Production of(RS)-1-(methylsulfinyl)-4-nitro-2-(trifluoromethyl)benzene

¹H-NMR (DMSO): 8.78 (m, 1H), 8.50 (m, 2H), 2.83 (s, 3H).

MS: 270 (ES).

tf) Production of (RS)-2-fluoro-1-(methylsulfinyl)-4-nitrobenzene

¹H-NMR (DMSO): 8.33 (m, 2H), 7.99 (m, 1H), 2.90 (s, 3H).

MS: 204 (ES).

u) Production of 1-(cyclopropylsulfanyl)-4-nitrobenzene

The cyclization of 1-(3-chloro-propylsulfanyl)-4-nitro-benzene wasperformed as described in J. Org. Chem., 33(1), 43-47 (1968).

¹H-NMR (DMSO): 8.18 (d, 2H), 7.60 (d, 2H), 2.40 (m, 1H), 1.21 (m, 2H),0.66 (m, 2H).

MS (CI): 195 (M⁺, 12%), 213 (M⁺+1+NH₃, 100%), 230 (M⁺+1+2NH₃, 44%).

v) Production of 1-[(3-chloropropyl)sulfanyl]-4-nitrobenzene

1 g of potassium hydroxide is dissolved in 40 ml of methanol and mixedwith 2.3 g of 4-nitrothiophenol. The suspension is stirred for one hourat room temperature and mixed drop by drop with 1.48 ml of1-bromo-3-chloropropane. After 4 hours of stirring at room temperature,another 0.15 ml of 1-bromo-3-chloropropane is added in drops. Themixture is stirred for 65 hours at room temperature, concentrated byevaporation in a vacuum and taken up in ethyl acetate. It is extractedwith water and saturated common salt solution, dried on sodium sulfateand concentrated by evaporation. After purification by flashchromatography, 2.54 g of 1-(3-chloro-propylsulfanyl)-4-nitro-benzene isobtained.

¹H-NMR (DMSO): 8.16 (d, 2H), 7.55 (d, 2H), 3.77 (t, 2H), 3.25 (t, 2H),2.08 (q, 2H).

MS (ES): 232 (100%), 234 (38%).

Produced in a similar way are also1-cyclopropylmethylsulfanyl-4-nitro-benzene (from(chloromethyl)-cyclopropane) and 1-cyclopentylsulfanyl-4-nitro-benzene(from bromocyclopentane).

w) Production of(RS)—S-(2-hydroxyethyl)-S-(4-nitrophenyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide

¹H-NMR (DMSO): 8.48 (m, 2H), 8.24 (m, 2H), 4.97 (tr, 1H), 3.99 (tr, 2H),3.79 (m, 2H), 3.00 (dd, 2H), 0.96 (m, 2H), 0.05 (s, 9H).

x) Production of (RS)—S-(4-amino-2-methoxyphenyl)-S-methylsulfoximide

1.5 g (6.5 mmol) of (RS)—S-(2-methoxy-4-nitrophenyl)-S-methylsulfoximidein 100 ml of ethanol is mixed with 300 mg of palladium on carbon(10%×50% H₂O) and hydrogenated for 45 minutes at room temperature andnormal pressure. The batch is filtered and concentrated by evaporation.1.0 g (5.1 mmol, corresponding to 79% of theory) of the product isobtained.

¹H-NMR (DMSO-D6): 7.10 (m, 1H), 6.92 (m, 1H), 6.73 (m, 1H), 4.70 (br,3H), 3.76 (s, 3H), 3.13 (s, 3H).

MS: 201 (ES).

y) Production of (RS)—S-(2-methoxy-4-nitrophenyl)-S-methyl sulfoximide

7.5 g of fuming nitric acid is cooled to −10° C. and slowly mixed with5.0 g (32.4 mmol) of 1-methoxy-2-methylsulfanyl-benzene. The batch isslowly heated to room temperature while being stirred, diluted with 100ml of water and neutralized with sodium bicarbonate. It is extractedwith diethyl ether and ethyl acetate. The combined organic phases aredried (Na₂SO₄), filtered and concentrated by evaporation.

5.3 g of the intermediate product that is obtained is mixed with 1.8 g(27.7 mmol) of sodium azide and 25 ml of CHCl₃. The batch is cooled to0° C. and carefully mixed with 6.3 ml of concentrated sulfuric acid. Itis heated first to room temperature and then to 45° C. The batch isstirred overnight at this temperature. After cooling, it is mixed with75 ml of ice water and 20 ml of CHCl₃. The organic phase is separated,and the aqueous phase is extracted again with 100 ml of CHCl₃. Theaqueous phase is made basic with 1N NaOH solution and then extractedfrom CHCl₃ (2×). The organic phases of the last extraction are combined,dried (Na₂SO₄), filtered and concentrated by evaporation. 3.8 g (16.5mmol) of the product is obtained.

¹H-NMR (DMSO-D6): 8.66 (m, 1H), 8.48 (m, 1H), 7.45 (m, 1H), 4.70 (s,1H), 4.08 (s, 3H), 3.21 (s, 3H).

MS: 231 (ES).

z) Production of (RS)—S-(2-methyl-4-nitrophenyl)-S-methyl sulfoximide

1.5 g (7.5 mmol) of (RS)-2-methyl-1-(methylsulfinyl)-4-nitrobenzene and1.1 g (17.1 mmol) of sodium azide in 10.0 ml of CHCl₃ are carefullymixed at 0° C. with 2.2 ml of concentrated sulfuric acid. The batch isheated first to room temperature and then to 45° C. while being stirredvigorously. It is stirred for 116 hours at this temperature. Aftercooling, it is mixed with water and extracted from DCM (2×). The aqueousphase is made basic with 2N NaOH solution and extracted from DCM. Thecombined organic phases are filtered through a Whatman filter andconcentrated by evaporation. The crude product that is obtained isrecrystallized from ethyl acetate. 1.3 g (6.1 mmol, corresponding to 81%of theory) of the product is obtained.

¹H-NMR (DMSO): 8.28 (m, 1H), 8.22 (m, 2H), 4.67 (s, 1H), 3.17 (s, 3H),2.81 (s, 3H). MS: 215 (ES).

za) Production of(RS)—S-methyl-S-[4-nitro-2-(trifluoromethyl)phenyl]sulfoximide

¹H-NMR (DMSO): 8.73 (m, 1H), 8.52 (m, 2H), 5.00 (s, 1H), 3.17 (s, 3H).

MS: 269 (ES).

zb) Production of (RS)—S-(2-fluoro-4-nitrophenyl)-S-methyl sulfoximide

¹H-NMR (DMSO): 8.34 (m, 1H), 8.24 (m, 1H), 8.10 (m, 1H), 5.08 (s, 1H),3.21 (s, 3H).

MS: 219 (ES).

zc) Production of (RS)—N,S-dimethyl-S-(4-nitrophenyl)sulfoximide

500 mg (2.5 mmol) of (RS)—S-(4-nitrophenyl)-S-methyl sulfoximide in 4 mlof formaldehyde (aqueous, 37%) and 20 ml of formic acid (98-100%) arestirred in an open flask at 100° C. After 22 hours, the solvent isevaporated, mixed again with 4 ml of formaldehyde (aqueous, 37%) and 20ml of formic acid (98-100%) and stirred for another 22 hours at 100° C.Residue from the solvent is drawn off in a rotary evaporator. Theremaining residue is dissolved with 2N HCl and extracted from DCM. Theaqueous phase is made basic with NaHCO₃ and extracted from DCM. Thecombined organic phases are dried (Na₂SO₄), filtered and concentrated byevaporation. 448 mg (2.1 mmol, corresponding to 85% of theory) of theproduct is obtained.

¹H-NMR (DMSO-D6): 8.43 (m, 2H), 8.08 (m, 2H), 3.24 (s, 3H), 2.48 (s,3H).

MS: 214 (ES).

zd) Production of(RS)—N-(ethoxycarbonyl)-S-methyl-S-(4-nitrophenyl)sulfoximide

8.50 g (42.5 mmol) of (RS)—S-(4-nitrophenyl)-S-methyl sulfoximide in 400ml of pyridine is mixed drop by drop at room temperature with 18.8 ml(197.2 mmol) of ethyl chloroformate. The batch is stirred for 4 hours atroom temperature and then added in dilute NaCl solution. It is extractedfrom ethyl acetate. The combined organic phases are dried (Na₂SO₄),filtered and concentrated by evaporation. The remaining residue ispurified by chromatography (hexane/ethyl acetate 1:1). 8.94 g (32.8mmol, corresponding to 77% of theory) of the product is obtained.

¹H-NMR (DMSO-D6): 8.49 (m, 2H), 8.22 (m, 2H), 3.90 (m, 2H), 3.56 (s,3H), 1.10 (tr, 3H).

ze) Production of(RS)—S-ethyl-N-({[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-oxy}carbonyl)-S-(4-nitrophenyl)sulfoximide

100 mg (0.47 mmol) of (RS)—S-(4-nitrophenyl)-S-ethyl sulfoximide in 4.40ml of pyridine is mixed drop by drop at room temperature with 0.46 ml(2.17 mmol) of (+) menthyl chloroformate. The batch is stirred for 4hours at room temperature and then added to dilute NaCl solution. It isextracted from ethyl acetate. The combined organic phases are dried(Na₂SO₄), filtered and concentrated by evaporation. The remainingresidue is purified by chromatography (hexane/ethyl acetate 1:1). 161 mg(0.41 mmol, corresponding to 87% of theory) of the product is obtained.

¹H-NMR (DMSO-D6): 8.49 (m, 2H), 8.13 (m, 2H), 4.28 (m, 1H), 3.67 (m,2H), 1.77 (m, 1H), 1.55 (m, 2H), 1.25 (m, 6H), 0.75 (m, 12H).

zf) Production of(RS)—N-(ethoxycarbonyl)-S-ethyl-S-(4-nitrophenyl)sulfoximide

¹H-NMR (DMSO-D6): 8.48 (m, 2H), 8.15 (m, 2H), 3.92 (m, 2H), 3.69 (m,2H), 1.12 (m, 6H).

zg) Production of(RS)—N-(ethoxycarbonyl)-S-methyl-S-(2-methyl-4-nitrophenyl)sulfoximide

¹H-NMR (DMSO): 8.33 (m, 2H), 8.17 (m, 1H), 3.90 (q, 2H), 3.55 (s, 3H),2.73 (s, 3H), 1.08 (tr, 3H).

MS: 287 (ES).

zh) Production of(RS)—N-(ethoxycarbonyl)-S-(2-fluoro-4-nitrophenyl)-S-methyl sulfoximide

¹H-NMR (DMSO): 8.45 (m, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 3.40 (m, 2H),3.60 (s, 3H), 1.04 (tr, 3H).

zi) Production of(RS)—N-(ethoxycarbonyl)-S-methyl-S-[4-nitro-2-(trifluoromethyl)phenyl]sulfoximide

¹H-NMR (DMSO): 8.78 (m, 1H), 8.65 (m, 1H), 8.49 (m, 1H), 3.90 (q, 2H),3.58 (s, 3H), 1.07 (tr, 3H).

zj) Production of (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide

A solution of 8.70 g (32.0 mmol) of(RS)—N-(ethoxycarbonyl)-S-methyl-S-(4-nitrophenyl)sulfoximide in 650 mlof THF is slowly mixed at room temperature with 435 ml of a 10% solutionof Ti(III)Cl in approximately 10% hydrochloric acid (Aldrich). The batchis stirred for 4 hours at room temperature and then cooled to 0° C. 450ml of a 32% NaOH solution is added in drops. In this case, the reactionmixture is now diluted by the addition of water and ethyl acetate. It ismixed with 500 ml of ethyl acetate, and the organic phase is separated.The pulpy, aqueous phase is extracted from ethyl acetate. The combinedorganic phases are washed with dilute NaCl solution, dried (Na₂SO₄),filtered and concentrated by evaporation. 8.05 g (about 32.0 mmol) ofthe product is obtained, and said product is used without furtherpurification.

¹H-NMR (DMSO-D6): 7.52 (m, 2H), 6.66 (m, 2H), 6.17 (m, 2H), 3.91 (q,2H), 3.30 (s, 3H), 1.12 (tr, 3H).

zk) Production of (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-ethylsulfoximide

¹H-NMR (DMSO-D6): 7.47 (m, 2H), 6.67 (m, 2H), 6.20 (s, 2H), 3.90 (m,2H), 3.42 (q, 2H), 1.10 (m, 6H).

zl) Production of(RS)—S-(4-aminophenyl)-S-(2-hydroxyethyl)-N-[2-trimethylsilyl)-ethylsulfonyl]sulfoximide

¹H-NMR (DMSO-D6): 7.54 (m, 2H), 6.68 (m, 2H), 6.30 (s, 2H), 4.90 (tr,1H), 3.68 (m, 4H), 2.95 (m, 2H), 0.95 (m, 2H), 0.01 (s, 9H).

zm) Production of(RS)—S-(4-amino-2-methylphenyl)-N-(ethoxycarbonyl)-S-methyl sulfoximide

¹H-NMR (DMSO-D6): 7.53 (m, 1H), 6.48 (m, 2H), 6.04 (s, 2H), 3.90 (q,2H), 3.30 (s, 3H), 2.42 (s, 3H), 1.13 (tr, 3H).

zn) Production of (RS)—S-(4-aminophenyl)-N,S-dimethyl sulfoximide

¹H-NMR (DMSO-D6): 7.48 (d, 2H), 6.62 (d, 2H), 5.95 (s, 2H), 2.95 (s,3H), 2.41 (s, 3H).

zo) Production of(RS)—S-(4-amino-2-fluorophenyl)-N-(ethoxycarbonyl)-S-methyl sulfoximide

¹H-NMR (DMSO): 7.45 (m, 1H), 6.48 (m, 4H), 3.88 (m, 2H), 3.30 (s, 3H),1.10 (tr, 3H).

zp) Production of(RS)—S-[4-amino-2-(trifluoromethyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulfoximide

¹H-NMR (DMSO): 7.78 (m, 1H), 7.12 (m, 1H), 6.84 (m, 1H), 6.63 (s, 2H),3.89 (q, 2H), 3.30 (s, 3H), 1.08 (tr, 3H).

MS: 311 (ES).

The examples below describe the biological action of the compoundsaccording to the invention without the invention being limited to theseexamples.

EXAMPLE 1 CDK1/CycB Kinase Assay

Recombinant CDK1- and CycB-GST-fusion proteins, purified frombaculovirus-infected insect cells (Sf9), were purchased from ProQinaseGmbH, Freiburg. Histone IIIS, used as a kinase substrate, is availablecommercially from the Sigma Company.

CDK1/CycB (200 ng/measuring point) was incubated for 15 minutes at 22°C. in the presence of various concentrations of test substances (0 μm,as well as within the range of 0.01-100 μm) in assay buffer [50 mmol oftris/HCl, pH 8.0, 10 mmol of MgCl₂, 0.1 mmol of Na ortho-vanadate, 1.0mmol of dithiothreitol, 0.5 μm of adenosine triphosphate (ATP), 10μg/measuring point of histone IIIS, 0.2 μCi/measuring point of ³³P-gammaATP, 0.05% NP40, 12.5% dimethyl sulfoxide]. The reaction was stopped byadding EDTA solution (250 mmol, pH 8.0, 14 μl/measuring point).

From each reaction batch, 10 μl was applied to P30 filter strips (WallacCompany), and non-incorporated 33P-ATP was removed by subjecting thefilter strips to three washing cycles for 10 minutes each in 0.5%phosphoric acid. After the filter strips were dried for one hour at 70°C., the filter strips were covered with scintillator strips (MeltiLex™A, Wallac Company) and baked for one hour at 90° C. The amount ofincorporated 33P (substrate phosphorylation) was determined byscintillation measurement in a gamma-radiation measuring device(Wallac).

EXAMPLE 2 CDK2/CycE Kinase Assay

Recombinant CDK2- and CycE-GST-fusion proteins, purified frombaculovirus-infected insect cells (Sf9), were purchased by ProQinaseGmbH, Freiburg. Histone IIIs, which was used as a kinase substrate, waspurchased by the Sigma Company.

CDK2/CycE (50 ng/measuring point) was incubated for 15 minutes at 22° C.in the presence of various concentrations of test substances (0 μm, aswell as within the range of 0.01-100 μm) in assay buffer [50 mmol oftris/HCl, pH 8.0, 10 mmol of MgCl₂, 0.1 mmol of Na ortho-vanadate, 1.0mmol of dithiothreitol, 0.5 μm of adenosine triphosphate (ATP), 10μg/measuring point of histone IIIS, 0.2 μCi/measuring point of ³³P-gammaATP, 0.05% NP40, 12.5% dimethyl sulfoxide]. The reaction was stopped byadding EDTA solution (250 mmol, pH 8.0, 14 μl/measuring point).

From each reaction batch, 10 μl was applied to P30 filter strips (WallacCompany), and non-incorporated ³³P-ATP was removed by subjecting thefilter strips to three washing cycles for 10 minutes each in 0.5%phosphoric acid. After the filter strips were dried for one hour at 70°C., the filter strips were covered with scintillator strips (MeltiLex™A, Wallac Company) and baked for one hour at 90° C. The amount ofincorporated ³³P (substrate phosphorylation) was determined byscintillation measurement in a gamma-radiation measuring device(Wallac).

EXAMPLE 3 VEGF Receptor-2 Kinase Assay

Recombinant VEGF receptor tyrosine kinase-2 was purified as a GST fusionprotein from baculovirus-infected insect cells (Sf9). Poly-(Glu4Tyr),which was used as a kinase substrate, was purchased by the SigmaCompany.

VEGF receptor tyrosine kinase (90 ng/measuring point) was incubated for10 minutes at 22° C. in the presence of various concentrations of testsubstances (0 μm, as well as within the range of 0.001-30 μm) in 30 μlof assay buffer [40 mmol of Tris/HCl, pH 5.5, 10 mmol of MgCl2, 1 mmolof MnCl2, 3 μmol of Na ortho-vanadate, 1.0 mmol of dithiothreitol, 8μmol of adenosine trisphosphate (ATP), 27 μg/measuring point ofpoly-(Glu4Tyr), 0.2 μCi/measuring point of 33P-gamma ATP, 1% dimethylsulfoxide]. The reaction was stopped by adding EDTA solution (250 mmol,pH 7.0, 10 μl/measuring point).

From each reaction batch, 10 μl was applied to P30 filter strips (WallacCompany), and non-incorporated 33P-ATP was removed by subjecting thefilter strips to three washing cycles for 10 minutes each in 0.5%phosphoric acid. After the filter strips were dried for one hour at 70°C., the filter strips were covered with scintillator strips (MeltiLex™A, Wallac Company) and baked for one hour at 90° C. The amount ofincorporated 33P (substrate phosphorylation) was determined byscintillation measurement in a gamma-radiation measuring device(Wallac). The IC50 values are determined from the inhibitorconcentration, which is necessary to inhibit the phosphate incorporationto 50% of the uninhibited incorporation after removal of the blankreading (EDTA-stopped reaction).

EXAMPLE 4 Proliferation Assay

Cultivated human tumor cells (MCF7, hormone-independent human breastcancer cells, related to ATCC HTB22; NCI-H460, human non-small-cell lungcancer cells, ATCC HTB-177, HCT 116, human colon cancer cells, ATCCCCL-247; DU 145, hormone-independent human prostate cancer cells, ATCCHTB-81; MaTu-MDR, hormone-independent, multiple pharmaceuticalagent-resistant human breast cancer cells, EPO-GmbH, Berlin) wereflattened out at a density of about 5000 cells/measuring point,depending on the growth rate of the respective cells, in a 96-wellmultititer plate in 200 μl of the corresponding growth medium. After 24hours, the cells of one plate (zero-point plate) were colored withcrystal violet (see below), while the medium of the other plates wasreplaced by fresh culture medium (200 μl), to which the test substanceswere added in various concentrations (0 μm, as well as in the range of0.01-30 μm; the final concentration of the solvent dimethyl sulfoxidewas 0.5%). The cells were incubated for 4 days in the presence of testsubstances. The cell proliferation was determined by coloring the cellswith crystal violet: the cells were fixed by adding 20 μl/measuringpoint of an 11% glutaric aldehyde solution for 15 minutes at roomtemperature. After three washing cycles of the fixed cells with water,the plates were dried at room temperature. The cells were colored byadding 100 μl/measuring point of a 0.1% crystal violet solution (the pHwas set at 3 by adding acetic acid). After three washing cycles of thecolored cells with water, the plates were dried at room temperature. Thedye was dissolved by adding 100 μl/measuring point of a 10% acetic acidsolution. The extinction was determined by photometry at a wavelength of595 nm The change of cell growth, in percent, was calculated bynormalization of the measured values to the extinction values of thezero-point plate (=0%) and the extinction of the untreated (0 μm) cells(=100%).

EXAMPLE 5 Carboanhydrase Assay

The principle of the assay is based on the hydrolysis of 4-nitrophenylacetate by carboanhydrases (Pocker & Stone, Biochemistry, 1967, 6, 668),with subsequent photometric determination of the dye 4-nitrophenolatethat is produced at 400 nm by means of a 96-channel spectral photometer.

2 μl of the test compounds, dissolved in DMSO (100× the finalconcentration), in a concentration range of 0.03-10 μm (final), waspipetted as 4× determinations into the holes of a 96-hole microtiterplate. Holes that contained the solvent without test compounds were usedas reference values (1. Holes without carboanhydrase for correction ofthe non-enzymatic hydrolysis of the substrate, and 2. Holes withcarboanhydrase for determining the activity of the non-inhibitedenzyme).

188 μl of assay buffer (10 mmol of Tris/HCl, pH 7.4, 80 mmol of NaCl),with or without 3 units/hole on carboanhydrase I or II, was pipettedinto the holes of the microtiter plate. The enzymatic reaction wasstarted by the addition of 10 μl of the substrate solution (1 mmol of4-nitrophenyl acetate (Fluka #4602), dissolved in anhydrous acetonitrile(final substrate concentration: 50 μm). The plate was incubated at roomtemperature for 15 minutes. The extinctions were measured by photometryat a wavelength of 400 nm The enzyme inhibition was calculated after themeasured values were normalized to the extinction of the reactions inthe holes without enzyme (=100% inhibition) and to the extinction ofreactions in the holes with non-inhibited enzyme (=0% inhibition).

The results from the examples and the comparison data are indicated inTables 1 to 3 below. To demonstrate the superiority of the compoundsaccording to the invention compared to the known compounds, thecompounds according to the invention were compared to known referencecompounds and a structurally similar known compound of Example 10 fromWO 00/096888 in the enzyme test. The result is indicated in Tables 1 and2 below. In Table 3, the improved data on the compounds according to theinvention are shown in comparison to the compound of Example 10 from WO00/12486 and acetazolamide.

TABLE 1 Proliferation IC₅₀ [μM] Example No. MCF7 H460 HCT116 DU145MaTu-ADR 1.0 0.3 1.2 0.4 1.5 1.6 2.0 1.5 0.3 0.3 1.7 0.4 1.3 <0.1 0.140.10 0.2 0.17 1.4 0.06 0.06 0.05 0.10 0.08 1.2 0.11 0.03 0.02 0.04 0.042.1 0.9 2.3 0.3 0.4 0.19 0.12 1.23 0.13 <0.1 0.1 <0.1 1.24 <0.1 0.070.13 0.08 1.25 <0.1 1.31 0.2 0.18 0.3 0.7 1.41 0.08 0.07 0.09 0.07 1.420.15 <0.1 0.17 <0.1 1.7 1.1 1.26 0.06 0.03 0.07 0.04 1.27 0.06 0.02 0.130.03 1.10 0.5 0.7 0.8 0.8 1.39 0.3 0.3 0.3 0.9 1.33 1 1.35 0.11 0.120.12 0.3 1.34 0.8 1.40 0.11 0.17 0.18 0.3 1.63 0.9 1.48 0.3 0.3 0.4 0.61.54 0.11 0.12 0.19 0.07 1.11 0.1 <0.1 <0.1 0.1 1.9 0.1 0.11 0.1 0.11.12 0.2 0.4 0.3 2.8 1.6 0.14 <0.1 <0.1 <0.1 1.37 0.17 <0.1 0.16 0.31.57 <0.1 0.12 0.11 0.09 1.49 0.3 0.4 0.3 0.6 1.50 1.2 1.55 0.3 0.3 0.30.15 1.56 0.02 0.1 0.07 0.05 1.46 0.2 0.11 0.17 0.2 1.47 0.6 0.6 0.6 0.81.16 0.18 0.2 0.19 4.0 1.20 0.2 0.4 0.4 2.1 1.38 0.12 0.06 0.13 0.4 1.360.14 0.12 0.17 1.2 1.51 0.08 0.05 0.05 0.06 1.60 0.06 0.04 0.04 0.041.14 0.09 0.10 0.09 0.11 1.15 0.18 0.2 0.3 0.3 1.32 0.19 0.18 0.3 0.61.28 0.17 0.12 0.2 0.2 3.4 1.0 3.5 0.12 0.05 0.06 0.03 1.58 0.06 0.030.03 0.04 1.59 0.11 <0.1 <0.1 <0.1 3.0 0.5 3.6 0.08 0.02 0.02 0.02 3.70.1 <0.1 <0.1 <0.1 3.8 0.4 0.3 0.3 0.19 3.1 0.4 1.29 0.17 1.30 0.17 3.100.4 3.9 1.0 1.18 <0.1 1.21 <0.1 1.52 <0.1 1.53 0.3 1.19 <0.1 1.43 <0.11.44 0.13 Example 10 from 0.4 0.6 0.4 0.7 0.8 WO 02/096888

TABLE 2 CDK2/CycE CDK1/CycB VEGF-R2 Example No. IC₅₀ [nM] IC₅₀ [nM] IC₅₀[nM] 2.0 16 110 70 1.0 <10 79 40 1.3 6 10 140 1.4 10 13 340 1.2 20 13048 2.1 390 >1000 74 2.3 33 160 61 1.23 6 8 75 1.24 8 5 150 1.25 3 2 701.31 9 27 140 1.41 2 2 76 1.42 2 5 64 1.7 >1000 >1000 240 1.26 4 2 311.27 4 3 97 1.10 >1000 >1000 910 1.39 19 49 150 1.33 51 200 450 1.35 4296 94 1.34 28 110 530 1.40 14 21 110 1.63 63 200 89 1.48 7 16 270 1.54 58 69 1.11 25 44 83 1.9 4 5 49 1.12 49 160 160 1.6 8 14 29 1.37 48 63 571.57 4 8 66 1.49 9 15 470 1.50 9 44 230 1.55 27 45 79 1.56 24 68 32 1.464 11 340 1.47 6 27 300 1.16 130 170 130 1.20 54 160 820 1.38 78 75 591.36 11 43 92 1.51 4 5 26 1.60 4 4 39 1.14 4 7 69 1.15 4 25 59 1.32 1216 56 1.28 7 14 37 3.4 41 72 250 3.5 8 17 150 1.58 7 4 45 1.59 7 9 483.0 16 49 170 3.6 18 22 200 3.7 11 19 110 3.8 27 91 >1000 3.1 33 97 1201.29 4 7 16 1.30 6 15 29 3.10 4 18 3.9 8 55 1.18 3 3 1.21 6 5 1.53 4 111.19 3 7 1.44 2 5 Example 10 from WO <10 90 200 02/096888

TABLE 3 Inhibition of Human Carboanhydrase-2 Example No. IC₅₀ [nM]Example 1.0 >10000 Example 2.0 >10000 Acetazolamide 51 Example 10 fromWO 190 02/096888

Tables 1 and 2 show that the compounds according to the inventioninhibit cyclin-dependent kinases and/or VEGF receptor tyrosine kinasesin the nanomolar range and thus can inhibit the proliferation of tumorcells and/or the tumor angiogenesis.

Table 3 shows that substances according to the invention, in contrast tocompounds from the prior art, such as, e.g., acetazolamide or Example 10from WO02/096888, which represents the closest prior art, do not haveany measurable carboanhydrase inhibiton and thus no longer exhibit apossible side effect that could be attributed to the carboanhydraseinhibition.

In this respect, the above-mentioned tables confirm that the substancesaccording to the invention are superior in comparison to the prior art.

The invention claimed is:
 1. Compounds of general formula (I)

in which Q stands for the group

[or] D, E, G, L, M and T, in each case independently of one another, stand for carbon, oxygen, nitrogen or sulfur, R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, CF₃, CN, nitro, or for the group —COR⁸ or —O—C₁-C₆-alkyl, R² stands for hydrogen, or C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, C₃-C₁₀-cycloalkyl, aryl or heteroaryl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, C₁-C₆-alkoxy, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, —C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, C₁-C₆-alkanoyl, —CONR⁹R¹⁰, —COR⁸, C₁-C₆-alkylOAc, aryl, heteroaryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁸, —(CH₂)_(n)PO₃(R⁸)₂ or with the group —R⁶ or —NR⁹R¹⁰, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and —(CH2)_(n)-heteroaryl itself optionally can be substituted in one or more places, in the same way or differently, with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, or with the group —CF₃ or —OCF₃, and the ring of C₃-C₁₀-cycloalkyl and C₁-C₁₀-alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more —C(O) groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, X stands for oxygen, sulfur, or for the group —NH— or —N(C₁-C₃-alkyl)- or X and R² together form a C₃-C₁₀-cycloalkyl ring, which optionally can contain one or more heteroatoms and optionally can be substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen or the group —NR⁹R¹⁰, R³ stands for hydrogen, hydroxy, halogen, CF₃, OCF₃ or for the group —NR⁹R¹⁰, or for C₁-C₆-alkyl, C₃-C₆-cycloalkyl or C₁-C₆-alkoxy that is optionally substituted in one or more places, in the same way or differently, with halogen, hydroxy, C₁-C₆-alkoxy or the group —NR⁹R¹⁰, m stands for 0-4, R⁴ stands for hydrogen or for the group —COR⁸, NO₂, trimethylsilanyl (TMS), tert-butyl-dimethylsilanyl (TBDMS), tert-butyl-diphenylsilanyl (TBDPS), triethylsilanyl (TES) or —SO₂R⁷ or for C₁-C₁₀-alkyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, cyano, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl or with the group —CONR⁹R¹⁰, COR⁸, —CF₃, —OCF₃ or —NR⁹R¹⁰, R⁵ stands for C₁-C₁₀-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, halogen or the group —NR⁹R¹⁰, or R⁴ and R⁵ together can form a C₅-C₁₀-cycloalkyl ring of group

whereby V, W and Y, in each case independently of one another, stand for —CH₂— that is optionally substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₁₀-alkyl, C₁-C₁₀-alkoxy or —NR⁹R¹⁰, whereby C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy also can be substituted in one or more places, in the same way or differently, with hydroxy, —NR⁹R¹⁰ or C₁-C₁₀-alkoxy and/or can be interrupted by one or more —C(O)— groups in the ring, and/or optionally one or more double bonds can be contained in the ring, R⁶ stands for a heteroaryl or a C₃-C₁₀-cycloalkyl ring, which optionally can contain one or more heteroatoms and optionally can be substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, R⁷ stands for C₁-C₁₀-alkyl or aryl that is optionally substituted in one or more places, in the same way or differently, with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group trimethylsilanyl (TMS) or —NR⁹R¹⁰, R⁸ stands for hydrogen, C₁-C₆-alkyl, hydroxy, C₁-C₆-alkoxy, C₁-C₆-alkylthio, benzoxy or —NR⁹R¹⁰, R⁹ and R¹⁰, in each case independently of one another, stand for hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy, hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, phenyl, heteroaryl or for the group —(CH₂)_(n)NR⁹R¹⁰, —CNHNH₂ or —NR⁹R¹⁰, or R⁹ and R¹⁰ together form a C₃-C₁₀-cycloalkyl ring that optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more —C(O)— groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and n stands for 1-6, as well as their isomers, diastereomers, enantiomers and/or salts.
 2. Compounds of general formula (I) according to claim 1, in which Q stands for aryl, R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, CF₃, CN, nitro, or for the group —COR⁸ or —O—C₁-C₆-alkyl, R² stands for hydrogen or C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, C₃-C₁₀-cycloalkyl, aryl or heteroaryl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, C₁-C₆-alkoxy, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, —C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, C₁-C₆-alkanoyl, —CONR⁹R¹⁰, —COR⁸, C₁-C₆-alkylOAc, aryl, heteroaryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n —R) ⁸, —(CH₂)_(n)PO₃(R⁸)₂ or with the group —R⁶ or —NR⁹R¹⁰, and the phenyl, C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and —(CH₂)_(n)-heteroaryl itself optionally can be substituted in one or more places, in the same way or differently, with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl and the C₁-C₁₀-alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more —C(O)— groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, X stands for oxygen, sulfur, or for the group —NH—, or —N(C₁-C₃-alkyl)- or X and R² together form a C₃-C₁₀-cycloalkyl ring, which optionally can contain one or more heteroatoms and optionally can be substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen or the group —NR⁹R¹⁰, R³ stands for hydrogen, hydroxy, halogen, CF₃, OCF₃ or for the group —NR⁹R¹⁰, or for C₁-C₆-alkyl, C₃-C₆-cycloalkyl or C₁-C₆-alkoxy that is optionally substituted in one or more places, in the same way or differently, with halogen, hydroxy, C₁-C₆-alkoxy or the group —NR⁹R¹⁰, m stands for 0-4, R⁴ stands for hydrogen or for the group —COR⁸, NO₂, trimethylsilanyl (TMS), tert-butyl-dimethylsilanyl (TBDMS), tert-butyl-diphenylsilanyl (TBDPS), triethylsilanyl (TES) or for —SO₂R⁷ or for C₁-C₁₀-alkyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, cyano, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl or with the group —CONR⁹R¹⁰, COR⁸, —CF₃, —OCF₃ or —NR⁹R¹⁰, R⁵ stands for C₁-C₁₀-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, halogen, or the group —NR⁹R¹⁰, or R⁴ and R⁵ together can form a C₅-C₁₀-cycloalkyl ring of the group

 whereby V, W and Y, in each case, independently of one another, stands for —CH₂—, which is optionally substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₁₀-alkyl, C₁-C₁₀-alkoxy or —NR⁹R¹⁰, whereby C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy also can be substituted in one or more places, in the same way or differently, with hydroxy, —NR⁹R¹⁰ or C₁-C₁₀-alkoxy and/or can be interrupted by one or more —C(O)— groups in the ring, and/or optionally one or more double bonds can be contained in the ring, R⁶ stands for a heteroaryl or a C₃-C₁₀-cycloalkyl ring, which optionally can contain one or more heteroatoms and optionally can be substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, R⁷ stands for C₁-C₁₀-alkyl or aryl that is optionally substituted in one or more places, in the same way or differently, with halogen, hydroxy, C₁-C₆-alkyl, or C₁-C₆-alkoxy or with the group trimethylsilanyl (TMS) or —NR⁹R¹⁰, R⁸ stands for hydrogen, C₁-C₆-alkyl, hydroxy, C₁-C₆-alkoxy, C₁-C₆-alkylthio, benzoxy or —NR⁹R¹⁰, R⁹ and R¹⁰, in each case independently of one another, stand for hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy, hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, phenyl, heteroaryl, or for the group —(CH₂)_(n)NR⁹R¹⁰, —CNHNH₂ or —NR⁹R¹⁰, or R⁹ and R¹⁰ together form a C₃-C₁₀-cycloalkyl ring that optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more —C(O)— groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and n stands for 1-6, as well as their isomers, diastereomers, enantiomers and/or salts.
 3. Compounds of general formula (I) according to claim 1, in which Q stands for phenyl, R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, CF₃, CN, nitro or for the group —COR⁸ or —O—C₁-C₆-alkyl, R² stands for hydrogen or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, C₃-C₁₀-cycloalkyl, aryl or heteroaryl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, C₁-C₆-alkoxy, amino, cyano, C₁-C₆-alkyl, —NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, —C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, C₁-C₆-alkanoyl, —CONR⁹R¹⁰, —COR⁸, C₁-C₆-alkylOAc, aryl, heteroaryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁸, —(CH₂)_(n)PO₃(R⁸)₂ or with the group —R⁶ or —NR⁹R¹⁰, and phenyl, C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and —(CH₂)_(n)-heteroaryl itself optionally can be substituted in one or more places, in the same way or differently, with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, or with the group —CF₃ or —OCF₃, and the ring of C₃-C₁₀-cycloalkyl and C₁-C₁₀-alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms, and/or can be interrupted by one or more —C(O)— groups in the ring, and/or optionally one or more possible double bonds can be contained in the ring, X stands for oxygen, sulfur, or for the group —NH— or —N(C₁-C₃-alkyl)-, or X and R² together form a C₃-C₁₀-cycloalkyl ring, which optionally can contain one or more heteroatoms, and optionally can be substituted in one or more places with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen or the group —NR⁹R¹⁰, R³ stands for hydrogen, hydroxy, halogen, CF₃, OCF₃ or for the group —NR⁹R¹⁰ or for C₁-C₆-alkyl, C₃-C₆-cycloalkyl or C₁-C₆-alkoxy that is optionally substituted in one or more places, in the same way or differently, with halogen, hydroxy, C₁-C₆-alkoxy or the group —NR⁹R¹⁰, m stands for 0-2, R⁴ stands for hydrogen or for the group —COR⁸, NO₂, trimethylsilanyl (TMS), tert-butyl-dimethylsilanyl (TBDMS), tert-butyl-diphenylsilanyl (TBDPS), triethylsilanyl (TES) or —SO₂R⁷, or for C₁-C₁₀-alkyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, cyano, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl or with the group —CONR⁹R¹⁰, COR⁸, —CF₃, —OCF₃ or —NR⁹R¹⁰, R⁵ stands for C₁-C₁₀-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, halogen or the group —NR⁹R¹⁰, or R⁴ and R⁵ together can form a C₅-C₁₀-cycloalkyl ring of the group

 whereby V, W, and Y, in each case independently of one another, stand for —CH₂— that is optionally substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₁₀-alkyl, C₁-C₁₀-alkoxy or —NR⁹R¹⁰, whereby C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy also can be substituted in one or more places, in the same way or differently, with hydroxy, —NR⁹R¹⁰ or C₁-C₁₀-alkoxy, and/or can be interrupted by one or more —C(O)— groups in the ring, and/or optionally one or more double bonds can be contained in the ring, R⁶ stands for a heteroaryl or a C₃-C₁₀-cycloalkyl ring, which optionally can contain one or more heteroatoms, and optionally can be substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, R⁷ stands for C₃-C₁₀-aryl or aryl that is optionally substituted in one or more places, in the same way or differently, with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group trimethylsilanyl (TMS) or —NR⁹R¹⁰, R⁸ stands for hydrogen, C₁-C₆-alkyl, hydroxy, C₁-C₆-alkoxy, C₁-C₆-alkylthio, benzoxy or —NR⁹R¹⁰, R⁹ and R¹⁰, in each case independently of one another, stand for hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy, hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, phenyl, heteroaryl or for the group —(CH₂)_(n)NR⁹R¹⁰, —CNHNH₂ or —NR⁹R¹⁰, or R⁹ and R¹⁰ together form a C₃-C₁₀-cycloalkyl ring, which optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more —C(O)— groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and n stands for 1-6, as well as their isomers, diastereomers, enantiomers and/or salts.
 4. Compounds of general formula (I) according to claim 1, in which Q stands for phenyl, R¹ stands for hydrogen, halogen, CN, NO₂ or CF₃, R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkinyl, aryl or heteroaryl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkinyl or with the group —COR⁸, X stands for oxygen, sulfur or for the group —NH—, R³ stands for hydrogen, halogen, hydroxy or C₁-C₆-alkyl or C₁-C₆-alkoxy that is optionally substituted in one or more places with halogen or hydroxy, m stands for 0-2, R⁴ stands for hydrogen or for the group NO₂, —CO—R⁸, —SO₂R⁷ or for C₁-C₁₀-alkyl that is optionally substituted in one or more places, in the same way or differently, with halogen or hydroxy, R⁵ stands for C₁-C₁₀-alkyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places, in the same way or differently, with hydroxy or C₃-C₁₀-cycloalkyl, or R⁴ and R⁵ together can form a C₅-C₁₀-cycloalkyl ring of the group

 whereby V, W and Y, in each case independently of one another, stand for —CH₂— that is optionally substituted in one or more places, in the same way or differently, with hydroxy, C₁-C₁₀-alkyl, C₁-C₁₀-alkoxy or —NR⁹R¹⁰, whereby C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy also can be substituted in one or more places, in the same way or differently, with hydroxy, —NR⁹R¹⁰ or C₁-C₁₀-alkoxy and/or can be interrupted by one or more —C(O)— groups in the ring and/or optionally one or more double bonds can be contained in the ring, R⁷ stands for C₁-C₁₀-alkyl that is optionally substituted in one or more places in the same way or differently, with the group trimethylsilanyl (TMS), R⁸ stands for hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy or C₃-C₆-cycloalkyl, which optionally can be substituted in one or more places with C₁-C₆-alkyl, n stands for 1, as well as their isomers, diastereomers, enantiomers and/or salts.
 5. Compounds of general formula (I) according to claim 1, in which Q stands for phenyl, R¹ stands for hydrogen or halogen, R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkinyl or aryl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkinyl or with the group —COR⁸, X stands for oxygen, sulfur or for the group —NH—, R³ stands for hydrogen, halogen or C₁-C₆-alkyl or C₁-C₆-alkoxy that is optionally substituted in one or more places with halogen, m stands for 0-2, R⁴ stands for hydrogen or for the group NO₂, —SO₂R⁷ or for C₁-C₁₀-alkyl, R⁵ stands for C₁-C₁₀-alkyl or C₃-C₁₀-cycloalkyl that is optionally substituted in one or more places, in the same way or differently, with hydroxy or C₃-C₁₀-cycloalkyl, R⁷ stands for C₁-C₁₀-alkyl that is optionally substituted in one or more places in the same way or differently, with the group trimethylsilanyl (TMS), R⁸ stands for hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy or C₃-C₆-cycloalkyl, which optionally can be substituted in one or more places with C₁-C₆-alkyl, as well as their isomers, diastereomers, enantiomers and/or salts.
 6. Compounds of general formula (I) according to claim 1, in which Q stands for phenyl, R¹ stands for hydrogen or halogen, R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkinyl or aryl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, methyl, methoxy, ethinyl or with the group —COH or —COCH₃, X stands for oxygen, sulfur or for the group —NH—, R³ stands for hydrogen, halogen, methyl, methoxy or —CF₃, m stands for 0-2, R⁴ stands for hydrogen, methyl or for the group NO₂, —COOC₂H₅ or —SO₂C₂H₄—Si(CH₃)₃, R⁵ stands for methyl, ethyl, cyclopropyl, cyclopentyl, —(CH₂)-cyclopropyl or hydroxyethyl, as well as their isomers, diastereomers, enantiomers and/or salts.
 7. In the method for preparing a compound of formula (I) according to claim 1, wherein the improvement is the use of a compound of general formula (IIa) or (IIb)

in which Z stands for —NH₂ or NO₂, and m, R³, R⁴ and R⁵ have the meanings that are indicated in general formula (I), as well as their isomers, diastereomers, enantiomers and/or salts as intermediate products for the production of the compound of general formula (I).
 8. A method according to claim 7, characterized in that m stands for 0-2, R³ stands for halogen, or for C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy that is optionally substituted in one or more places with halogen, R⁴ stands for hydrogen or for the group NO₂, —SO₂—R⁷, —CO—R⁸ or for C₁-C₁₀-alkyl, whereby R⁷ and R⁸ have the meaning that is indicated in general formula (I), and R⁵ stands for C₁-C₁₀-alkyl or C₃-C₆-cycloalkyl that is optionally substituted in one or more places with halogen or hydroxy.
 9. In a method for preparing a compound of formula (I) according to claim 1, wherein the improvement is the use of a compound of general formula (IIIa), (IIIb) or (IIIc),

in which W stands for halogen, hydroxy or X—R², and R¹, R², R³, R⁵, m and X have the meanings that are indicated in general formula (I), as well as their isomers, diastereomers, enantiomers, and/or salts as intermediate products for the production of the compound of general formula (I).
 10. A method according to claim 9, wherein R¹ stands for halogen, X stands for —NH—, R² stands for C₁-C₁₀-alkyl that is optionally substituted in one or more places with hydroxy, m stands for 0, and R⁵ stands for C₁-C₁₀-alkyl.
 11. In a method for preparing a compound of formula (I) according to claim 1, wherein the improvement is the use of a compounds of general formula (IV),

in which Hal stands for halogen, Y stands for halogen, hydroxy or X—R₂, and R₁, R₂ and X have the meanings that are indicated in general formula (I), as well as their isomers, diastereomers, enantiomers and/or salts as intermediate products for the production of the compound of general formula (I).
 12. A method according to claim 11, in which X stands for oxygen, sulfur or —NH—, R¹ stands for halogen, R² stands for C₁-C₁₀-alkyl or C₂-C₁₀-alkinyl that is optionally substituted with hydroxy, C₁-C₆-alkoxy or with the group —CO—R⁸, whereby R⁸ has the meaning that is indicated in general formula (I).
 13. Pharmaceutical agent that comprises a compound of general formula I according to claim 1, and a pharmaceutically acceptable carrier.
 14. A method for treating cancer selected from breast, lung, colon, and prostate cancers comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim
 1. 15. A method for inhibiting a cyclin-dependent kinase selected from CDK1 and CDK2 comprising administering to a subject in need thereof an effective amount of a compound of claim
 1. 16. A method for inhibiting VEGF-receptor tyrosine kinases comprising administering to a subject in need thereof an effective amount of a compound of claim
 1. 17. The method according to claim 14, in which the cancer is breast cancer.
 18. The method according to claim 14, in which the cancer is lung cancer.
 19. The method according to claim 14, in which the cancer is colon cancer.
 20. The method according to claim 14, in which the cancer is prostate cancer. 